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11 ANNALS OF THE ACTMVolume 15 Number 1

ANNALS OF THE ACTMAN INTERNATIONAL JOURNAL OFTROPICAL & TRAVEL MEDICINE

Official Journal of The Australasian College of Tropical MedicineVolume 15 Number 1 May 2014

ISSN 1448-4706

IN THIS ISSUETHE pHySiCAL HEALTH iMpACTS OF TrOpiCAL CyCLONES

ViTAMiN A, ZiNC, irON ANd iOdiNE iNTErVENTiONS iN CHiLdrEN UNdEr FiVE yEArS OF AgE

HEAriNg LOSS iN MALAriA

TB Or NOT TB: THE CLiNiCAL ANd diAgNOSTiC CHALLENgE OF SUSpECTEd pEriCArdiAL TUBErCULOSiS

AN UNUSUAL CASE OF Q FEVEr iN AN iMMUNiSEd SHEEp OFFiCEr

MAY 2014CONTENTS

Cover photo: The Australian Institute of Tropical Medicine in 1916 (photo courtesy of James Cook University)

ANNALS OF THE ACTMAN INTERNATIONAL JOURNAL OF TROPICAL & TRAVEL MEDICINE

EDITORIALChanging of the editorial guard!

peter A Leggat �� 1

REVIEw ARTICLESThe physical health impacts of tropical cyclones

rob d Mitchell, peter Aitken and richard C Franklin �� 2

Vitamin A, zinc, iron and iodine interventions in children under five years of age

Benjamin Wood �� 8

Hearing loss in malaria

Eric Fong �� 11

CASE REPORTTB or not TB: The clinical and diagnostic challenge of suspected pericardial tuberculosis

Victoria g Hall �� 16

CASE REPORTAn unusual case of Q fever in an immunised sheep officer

Frank C H Ng and peter A Leggat �� 19

© Copyright 2014 ACTM

Material published in the Annals of the ACTM is covered by copyright and all rights are reserved, excluding “fair use”, as permitted under copyright law� permission to use any material published in the Annals of the ACTM should be obtained in writing from the authors and Editorial board�

Officers of The Australasian College of Tropical MedicinePresident professor John McBride

President Elect Associate professor peter Nasveld

Vice President dr Kym daniell

Honorary Secretary dr Colleen Lau

Honorary Treasurer professor peter A� Leggat, AM

Council Members Associate professor geoff Quail, OAM, professor Marc Shaw, Emeritus professor richard Speare, AM, professor Bart Currie, Associate professor david porter, dr John Heydon

Chair, Faculty of Travel Medicine professor peter A� Leggat AM (Acting)

Chair, Faculty of Expedition and Wilderness Medicine professor Marc Shaw

Chairs of Standing Committees professor Tim inglis (disaster Health) dr richard S� Bradbury (Medical parasitology & Zoonoses) Associate professor John Frean (publications) dr Ken d� Winkel (Toxinology)

Secretariat ACTM Secretariat, pO Box 123, red Hill QLd 4059 AUSTrALiA Tel: +61-7-3872-2246 Fax: +61-7-3856-4727 Email: actm@tropmed�org Website: http://www�tropmed�org

Editorial BoardANNALS OF THE ACTM

Editor-in-Chief Associate professor John Frean

Emeritus Editor-in-Chief professor John M� goldsmid professor derek Smith

Executive Editor professor peter A� Leggat, AM

ACTM Newsletter

Editor ACTM Newsletter Wayne pederick

Board Members and Review Panel dr irmgard Bauer, Emeritus professor roderick SF Campbell, AM, professor david durrheim, dr Michael Humble, Associate professor Tim inglis, professor Ahmed Latif, dr Alan Mills, professor John H� pearn, AO, rFd, dr Ken d� Winkel


EDITORIALCHANgiNg OF THE EdiTORiAl guARd!

it is with great pleasure to have the opportunity to introduce and formally welcome Associate professor John Frean (see image at left) as the new Editor-in-Chief of the Annals of the ACTM� John Frean is in the National institute for Communicable diseases, and Associate professor, University of the Witwatersrand, Johannesburg, South Africa� John Frean has played a

number of key roles in the College, including being a member of the ACTM College Council� in his new role, he also chairs the publication Committee of the College, which has the Annals as its flagship publication, now in its 14th Volume�

Associate professor John Frean takes over the reins of the Annals from professor derek Smith (see image at right) from the University of Newcastle, Australia� derek Smith was appointed Editor-in-Chief of the Annals of the ACTM in 2008� Under derek’s stewardship, two issues of the Annals were published each year in January and June/July commencing with Volume 9 (2008) through to Volume 13 (2012)� Abstracts from various ACTM symposia and the Townsville Hospital Week were also included in one of the issues, particularly in more recent years. Derek Smith also produced the first special issue of the Annals and also a consolidated index in Volume 10

3389

8_JC

U103

3_MA

KADS

Public Health & Tropical Medicine At the Anton Breinl Centre

Public Health and Tropical Medicine at the Anton Breinl Centre seeks to undertake high quality and relevant teaching, research and training in population health, with a special focus on tropical Australia and our neighbours.

Postgraduate study programs: • Public Health and Tropical Medicine • Aeromedical Retrieval • Biosecurity and Disaster Preparedness

• Public Health • Communicable Disease Control • Health Promotion

• Disaster and Refugee Health • Tropical Medicine and Hygiene • Travel Medicine

For further information: Phone: +61 7 4781 5836 Email: [email protected] Web: www.jcu.edu.au/phtmrs

(issue 1, 2009) to celebrate 15 years of the Annals (1995-2009)� With Associate professor John Frean taking over the helm as Editor-in-Chief, the College conferred the title of Editor-in-Chief Emeritus for his dedicated service to the Annals over a period of 5 years� derek Smith continues to hold senior appointments on editorial boards of several journals, particularly in the field of occupational and environmental health and safety.

professor derek Smith is the second Editor-in-Chief to be conferred the title of Editor-in-Chief Emeritus� derek succeeded Emeritus professor John goldsmid, who had transitioned the Annals from an irregularly published monograph series to a peer-reviewed journal� John goldsmid also ensured that the Annals was published in full colour publication by the end of 2007, which encouraged the use of colour images� Following his retirement, Emeritus Professor John Goldsmid was confirmed as the inaugural Editor-in-Chief Emeritus in 2007, but continued to make contributions to various College publications� A College award, the John goldsmid Award, has been dedicated to John’s contributions to the journal and is awarded to the best paper published in the Annals each year�

Professor Peter A. leggat, AM Executive Editor, Annals of the ACTM, and Head, School of public Health, Tropical Medicine and rehabilitation Sciences, James Cook University, Townsville, Queensland, Australia�

2 ANNALS OF THE ACTM May 2014

REVIEw ARTICLE

The physical health impacts of tropical cyclonesRob d Mitchell,1 Peter Aitken,1,2 and Richard C Franklin2

1 Department of Emergency Medicine, Townsville Hospital, Townsville, Queensland, Australia

2 School of Public Health, Tropical Medicine & Rehabilitation Sciences, James Cook University, Townsville, Queensland, Australia

ABSTRACT

Tropical cyclones, also known as typhoons and hurricanes, are low-pressure weather systems characterised by extremely fast rotational winds� They dis-proportionately affect developing countries and have the potential to seri-ously disrupt basic societal functions� Like other natural disasters, cyclones also impact on health� This literature review considers the epidemiology of these events in terms of trauma, communicable disease and non-communi-cable disease�

Trauma is a significant cause of morbidity and mortality, although mecha-nisms vary between events� Both drowning and building collapse can lead to large numbers of fatalities� Minor injuries represent the primary cause of morbidity in the post-impact phase but carbon monoxide poisoning from inappropriate generator use is emerging as an important risk in both adult and paediatric patients� While communicable disease outbreaks are uncom-mon in developed settings, gastroenteritis, vector-borne disease and acute respiratory illness pose particular problems in developing communities� Non-communicable disease constitutes a considerable proportion of health-care attendances following cyclones, and exacerbations as well as treatment disruptions of chronic diseases are increasingly being recognised as a cause of cyclone-related morbidity and mortality�

Although Australia has well-developed public health infrastructure, major cyclones still have the potential to cause significant human suffering. This review will assist tropical communities in planning for these severe weather events. Implicit in its findings is the importance of injury prevention strate-gies, communicable disease surveillance and provision for managing chron-ic illnesses�

Keywords: cyclones, hurricanes, typhoons, trauma, disease, communicable, non-communicable

Ann Australas Coll Trop Med 2014;15(1):2-8.

BackgroundTropical cyclones, also known as typhoons and hurricanes, are low-pressure weather systems that develop over warm ocean waters� They are character-ised by extremely fast rotational winds that are generally in excess of 100 km/h�1 Approximately 119 million people are affected by an average of 80-90 individual cyclone systems each year,2,3 making them one of the most com-mon natural disasters worldwide�4

As cyclogenesis requires warm ocean waters, cyclones typically occur between the latitudes of 30 degrees north and 30 degrees south� regions within 500 kilometres of the equator are spared because cyclonic winds ro-tate in different directions in the two hemispheres� As a consequence of this distribution, cyclones predominantly affect developing communities� Of 84 nations with a history of recurrent exposure to cyclonic events, only a small minority (including Australia, New Zealand, Japan and the United States of America) are high-income countries�2

The human and environmental impacts of cyclone activity are the result of strong winds, heavy rainfall and storm surge, which often lead to landslides and flooding.1,5,6 In Australia, severity is rated using a five-category system based on wind velocity�7 Category four and five cyclones are expected to result in significant structural damage. Different rating systems are used in-ternationally (such as the Saffir/Simpson Scale in North America) and vary principally according to how wind speed is measured (Figure 1)�7,8

Cyclones have the potential to cause significant morbidity and mortality. They are estimated to have contributed to 1�9 million deaths in the last two centuries, and approximately 250,000 in the period 1980-2000�2,9 Their ef-fects on health can be both direct (as a result of severe weather forces) and indirect (as a result of infrastructure damage, environmental devastation, population displacement and economic hardship)� Historically, developing nations of the Asia-Pacific region have experienced the greatest absolute and proportionate mortality from tropical cyclones and other natural disasters�2

in Australia, cyclones in the last 150 years are estimated to have caused approximately 2,000 deaths, with a financial cost in excess of 6 trillion dol-lars�10 Over half of these deaths were caused by just five events occurring in a 50-year period from the late 1800s to the early 1900s (Figure 2)� Cyclone Mahina (Cooktown, 1899) led to over 400 fatalities, representing the sixth highest death toll from any disaster in Australia since 1850�10 in more recent memory, Cyclone Tracy (darwin, 1974) resulted in 71 deaths and approxi-mately 650 injuries�11

Although cyclone-related morbidity and mortality in the last two decades has been relatively small,10 recent events have illustrated the ongoing potential for harm. Cyclone Yasi, a category five system, brought winds in excess of 285 km/h when it crossed the Queensland coast near Mission Beach in February 2011�12 Although Queensland escaped without a major impact on health, the cyclone still led to at least one death13 and a record number of at-tendances to Townsville Hospital Emergency department (personal commu-nication, p Aitken)� The event also prompted the evacuation of both of Cairns’ hospitals (public and private), necessitating the transportation of over 350 patients to Brisbane (approximately 1700 km south)�14,15

The threat posed by tropical cyclones is unlikely to abate� As a consequence of global warming and rising sea temperatures, the frequency and intensity of extreme weather events is expected to increase�16-18 Consistent with this, upward trends have been observed in the estimated lifetime-maximum wind speeds of the very strongest tropical cyclones (above the 99th percentile) over each ocean basin�19

given the ongoing threat of tropical cyclones in northern Australia and the Asia-Pacific,1,2,7 it is appropriate to consider their potential impact on hu-man health� While severe cyclone activity is known to have psychological

Satellite image originally processed by the Bureau of Meteorology from the geostationary meteorological satellite MTSAT-2 operated by the Japan Meteorological Agency.

Cyclone yasi crossing the Queensland coast, February 2011


sequelae,1 the consequences for mental health are beyond the scope of this paper� This literature review builds on a comprehensive analysis by Shultz et al published in 20051 and includes a specific focus on epidemiological data from recent events. It has been designed to capture the significant amount of literature produced in the wake of Hurricane Katrina (United States of America, 2005)�

MethodspubMed was keyword and MeSH term searched for ‘health’ with each of ‘cyclone’, ‘hurricane’ and ‘typhoon’� results were limited to human data, English language and the last seven years (April 2005 – March 2012), as the 2005 review by Shultz et al1 was assumed to have included relevant peer-reviewed literature up until its publication date�

This broad search strategy identified 813 articles, most of which (62%) did not directly address the review question: 180 were only concerned with men-tal health, 246 were unrelated to health impacts or cyclones and 82 were editorials or opinion pieces� The abstracts of the remaining papers were re-viewed and a majority were found to be qualitative in nature� Full text was obtained for the relevant articles and bibliographies of key references were scanned for applicable articles, book chapters and grey literature (Figure 3)�

The 105 papers identified using this strategy were considered alongside the primary references quoted by Shultz et al (where accessible). They identified 151 relevant studies and reports, including those related to mental health�1

The results of this search confirm that the volume of literature related to trop-ical cyclones has grown significantly since 2005. In keeping with historical experience, most of the recent papers are retrospective descriptive studies�

in the discussion below, prominence has been given to more recent data� Where studies referred to the same data set, only one has been referenced� Findings are presented in the categories of trauma, communicable disease and non-communicable disease�

discussionTrauma

Trauma constitutes the majority of cyclone-related morbidity, and may occur pre-impact, at impact or post-impact�1,6 pre-impact injury tends to be the re-sult of preparation efforts, including reinforcing buildings, preparing genera-tors and cleaning outdoor areas� impact-related trauma relates to the direct impacts of destructive winds, heavy rain and storm surge, as well as the flooding and landslides that may result. Potentially harmful consequences of these forces include structural collapse, wind-blown debris, falling trees and downed power-lines� post-impact trauma is largely a consequence of clean-up related activities as well as the loss of normal public services� injury

Source: Emergency Management Australia

Figure 1 Tropical cyclone severity categories

Figure 2 Cyclone-related deaths in Australia 1871-2010

Figure 3 Search strategy

36

Figure 3. Search strategy

813 identified using search

strategy

180 excluded for relating only to mental health

246 excluded for being unrelated to health or tropical

cyclones

82 excluded for being editorials or

commentary

105 included

200 excluded for being qualitative, commentary or primarily mental health related

305 reviewed for relevance and new

data

Tropical Cyclone Severity Categories

10-minMean Wind

1-min

AustralianCategories

ONE TWO THREE FOUR FIVEUS SaffirSimpson

Max Gust

Knots

Knots

Km/h

30 40

40

40

50

50

60

60

60

70

70

80

80

80

90

90

100

100

100

110

110

120

120

120

130

130 140

140

150

160 180

80 100 120 140 160 180 200 220 240 260 280 300 320 340

Source: Australian Government Bureau of Meteorology (http://www.bom.gov.au/cyclone/faq/index.shtml#definitions)


can be associated with utilities damage and the subsequent requirements for temporary measures (including stored water and power generators)�1,6

Morbidity and mortality related to each of these stages varies according to the degree of development� deaths tend to be highest in the impact phase in developed settings, whereas developing communities tend to be affected to a greater extent in the wake of the storm front�1,6,20-22

data from Hurricane Katrina found that certain groups are at higher risk of trauma (and other health impacts) following cyclones� These include elderly, homeless, poor, unemployed and non-English speaking citizens as well as certain racial and ethnic groups�23-29 A recent study has identified that many of these groups are less likely to receive emergency broadcasts and evacua-tion orders, placing them at higher risk of trauma�30

Drowning

drowning has traditionally been the major cause of cyclone-related deaths, and typically results from storm surge and flooding in the immediate wake of the event�31 in recent times, the risk of drowning has been mitigated by the introduction of advanced warning, evacuation and shelter systems�1,5,32

Despite these developments, drowning still constitutes a significant pro-portion of cyclone-related mortality� in the United States of America (US), 40% of the 971 deaths directly attributed to Hurricane Katrina (2005) were thought to result from drowning�29 An empirical relationship between the depth of flooding water and mortality has been described.26 Following Hur-ricane Ike (2008), drowning constituted only 7% of overall deaths but was the most frequent cause of those directly related to the storm�33 Similar rates have been seen following other US events�34

Although limited data is available for developing settings, there are reports of drowning causing large numbers of fatalities following cyclones in Ban-gladesh, Mexico and the philippines�1,35 On the contrary, however, Typhoon Ranamin in China (2004) resulted in no deaths due to drowning but a signifi-cant number as a result of building collapse�36

Minor injuries

Minor injuries have been observed to constitute over 70% of presentations following tropical cyclones in developed countries�1,6,21,34 Most emergency department visits occur when weather conditions have stabilised�22,37

A 1993 review of cyclone-related injuries found significant variation in the patterns between events, as well inconsistency in the classification and cod-ing of injuries�6 in recent events, a wide spectrum of injuries has again been observed, including puncture wounds, lacerations, abrasions, contusions, sprains and fractures�34 Following Hurricane Katrina, the commonest pre-sentations were for lacerations, blunt trauma and puncture wounds29 and the most frequently reported mechanisms were falls and cuts�38 in other settings (eg, Cyclone gonu in Oman, 2007) orthopaedic injuries and lacerations have predominated�39

Although lower limb injuries were common among Hurricane Katrina evacu-ees in the Houston Astrodome/reliant park Complex site,40 this has not been the experience with other US events�34 Following Hurricane Andrew (1992), the most common body parts affected in non-fatal injuries were the upper extremities, including the fingers, hands, and arms.34,41 A recent review of all cyclone-related injuries presenting to emergency departments in Hong Kong over a six-year period supports this observation� in that study, the head (33.5%) and upper limbs (32.5%) were most often involved, with falls the commonest mechanism of injury (42.6%).21�40 Together, these data confirm that injury patterns following tropical cyclones are highly variable�

A recent study from the US has found that older citizens who were displaced from their homes had an increased fracture risk extending to 12 months following Hurricane Katrina�42 This persisted after controlling for other risk factors� rates of accelerant-related burn injuries have also been noted to increase following hurricane seasons in the US, which is possibly related to the burning of cyclone-generated debris�43

Major injuries

Life-threatening injuries may also result from tropical cyclones and tend to occur during the impact phase� For instance, following Cyclone ike in the US, 47 (64%) of all deaths resulted from injuries, compared with 23 (31%) from illnesses� Nine percent of overall deaths were caused by falling trees�44 Fol-lowing Katrina, 25% of deaths were attributed to injury and trauma, and older people were disproportionately affected�29 Motor vehicle accidents, chain-saw injuries, electrocutions and blunt trauma in the post-impact phase have also been reported�1,5,29,44

in a developing context, collapsed buildings were the most frequent cause of death following Typhoon rananim in China (2004)� Flying debris, collapsing buildings and motor vehicle collisions together caused 46% of all significant injuries� in that event, staying outdoors and not receiving (or ignoring) the typhoon alert were found to be statistically significant risk factors for serious injury�36

Carbon monoxide poisoning

Cyclone-related carbon monoxide poisoning was first described more than twenty years ago,45 but is increasingly reported as a major cause of morbid-ity�33,37,45-51 A majority of cases relate to the use of generators following power outages�

Following Cyclone ike, thirteen deaths were attributed to CO poisoning and at least fifteen individuals required treatment with hyperbaric therapy.33,46 it was estimated that 82-87% of exposures were the result of improper generator use, and children were disproportionately affected�46,47 At one hospital, 54% of 37 individuals presenting with CO poisoning were under the age of 18, and 75% of these resulted from generator-powered television or video-game use�47 in Australia, the one death attributed to Cyclone yasi (2011) was re-portedly the result of asphyxiation from inappropriate generator use�13

Communicable diseases

infectious disease outbreaks are not a major cause of morbidity following tropical cyclones�1,52-54 As with other disasters, the risk of outbreaks is asso-ciated with the size, health status and living conditions of the affected popu-lation� Crowding, inadequate water and sanitation, as well as poor access to health services, increase the risk of disease transmission�52,53,55,56 For these reasons, outbreaks tend to occur in developing countries far more frequently than they do in developed environments and almost always manifest in the post-impact phase�1,55,56

Diarrhoeal disease

diarrhoeal disease is the commonest infectious consequence of cyclone activity and is frequently the only reported communicable challenge in de-veloped countries�1,52 A variety of causative pathogens have been reported, which differ between settings based on local endemicity�56

Outbreaks of gastroenteritis have been documented following some cyclones in the US�57-62 Most recently, surveillance systems detected a norovirus out-break in a large evacuation centre in the aftermath of Hurricane Katrina�57-59 At a temporary medical facility erected at the reliant park Complex site, 1,173 patients were treated for gastroenteritis, representing 17% of all clinic visits and 4% of all patients who resided there for nine days.58 On the peak days, 40% of all paediatric presentations were for diarrhoea.57 While not all disease shelters experienced outbreaks, 61 sporadic cases of Salmonella spp� and toxigenic and non-toxigenic Vibrio cholerae were also reported�62

diarrhoeal disease outbreaks have been reported with greater frequency in developing countries�52,53,63-67 recent examples include Cyclone Aila, in West Bengal, india (2008),65,66 hurricanes gustav and ike in Cuba (2008)68 and Cyclone Nargis in Burma (2008)�67 in the latter, recently published data describes a four-fold increase in severe watery diarrhoea (suspected chol-era) in the immediate wake of the event� The overall incidence of diarrhoea increased from 571 per 100,000 persons per year in 2007 to 799 in the post-Nargis months of 2008� rates of dysentery also peaked sharply but had no impact on mortality�67 Following Aila, increases in diarrhoeal rates of


between 30 and 60% were seen in affected districts. Vibrio cholerae (54%) was the commonest agent, followed by Shigella spp. (5%).66 in Cuba, at least a 10% increase in gastroenteritis was seen following cyclones Gustav and ike�68 More recently, reports have emerged of increased diarrhoeal disease following typhoon events in the philippines�69

Acute respiratory infections

As with other natural disasters and situations involving displaced persons and overcrowded shelters, cyclones carry an increased risk of acute respira-tory infection�52,53,70 Like diarrhoeal illness, developing settings are dispro-portionately affected�

The most recently published data describes a peak in the incidence of acute respiratory infections (Ari) following Cyclone Nargis� A rate of 4,042 per 100,000 persons per year among children under 5 increased to 7,280 in 2008 following the event; it then fell back to 4,662 in 2009�67 More profound increases were seen in Nicaragua in the 30 days following Hurricane Mitch (1998), where a four-fold rise in incidence was reported�63

There are few reports of epidemic Ari following cyclones in developed set-tings� While some data suggested an increased number of adult presenta-tions with acute respiratory infection in the wake of Hurricane Katrina, the trend was attributed to multiple cases among a single National guard bat-talion�71 There was, however, a significant spike in the number of cases of Ari among children and adolescents, which was thought to be associated with increased environmental exposures�72 Firefighters exposed to floodwa-ter reported increased rates of upper respiratory tract infection symptoms�73

Wound infections

despite the theoretical risk of wound infections following cyclonic activity, there is little published data to support this. This may reflect reporting bias.

Following Hurricane Katrina, primary care providers noted a large number of wound infections on the lower limbs, but the severity has not been quanti-fied.74 After Hurricane ivan hit grenada in 2004, there was an increase in the number of patients admitted to surgical facilities as a result of wound complications and diabetic foot infections�75

A single Centers for disease Control and prevention report describes 18 cas-es of Vibrio spp�-infected wounds following Hurricane Katrina� Most patients had associated co-morbidities, and many had been wading in flood-waters. Five of these individuals subsequently died�76 in the wake of the same event, one hospital receiving evacuees identified a link between the presence of a wound and colonisation with multi-drug resistant organisms, but the nature of the association remains unclear�77

Sexually transmitted infections

A small number of reports from the US suggest that the incidence of sexu-ally transmitted infections may increase following cyclones�78,79 This has not been reported in developing regions affected by cyclones,67 but may reflect the integrity of surveillance systems�

Following Katrina, the prevalence of gonorrhoea in high school students in-creased from 2.3% (8/346) to 5.1% (17/333). Although of weak statistical significance, there was an independent positive trend toward testing positive for gonorrhoea after the hurricane� The exact reason for this is not yet under-stood, and the results may represent sampling error�78

There is also emerging data from the US about adverse impacts on human immunodeficiency virus (HIV).79-82 One study has reported a link between Katrina-associated post-traumatic stress disorder (pTSd) and viral replica-tion� Those with pTSd were more likely than those without pTSd to have detectable plasma viral loads and Cd4 cell counts <200/mm3 two years post-disaster� in addition, they were more likely to have had anti-retroviral inter-ruptions as a consequence of the event�79 robinson et al have also recently suggested that residential displacement might impact on Cd4 counts�80

These effects are unlikely to be cyclone specific.

Vector-borne diseases

Cyclones have the potential to impact on the transmission of vector-borne

diseases by changing vector distribution and breeding sites� As with other communicable diseases, the subsequent risk of outbreaks is compounded by crowding, loss of shelter, weakened public health systems and the in-terruptions of ongoing control programs�83 Outbreaks can only occur if the disease is endemic in the region prior to the event�84

While increases in vector population following cyclones have been docu-mented (examples include Belize post-Alma in 2008 and Mexico post-isidore in 2002),85,86 the extent to which this has translated to disease is variable� While cases of malaria have peaked sharply in some settings,87 they have been seen to decline in others�85 recently-published data describes an in-crease in malaria cases following Cyclone Nargis, but it is uncertain if this is a reflection of normal seasonal variation or a post-disaster phenomenon.67

Some have hypothesised that, in certain settings, the risk of arboviral infec-tions might surpass the risk from other vector-borne diseases�85 This is sup-ported by evidence of significant spikes in dengue cases following Cyclone Mitch�84,87

Evidence of vector-borne disease in developed settings is slim� While there were concerns about a potential outbreak of West Nile virus following Hur-ricane Katrina, this did not occur to a significant extent.49,88 One group has reported that no mosquitoes collected from the gulf Coast in the six weeks following that event had evidence of arbovirus infection�89 There is, however, data to support an increase in the incidence of animal bites and stings among exposed persons�1,48,54

Leptospirosis

Leptospirosis is a zoonotic disease that has potential to cause significant morbidity, primarily as a result of acute renal failure� it has been commonly described following cyclones in developing settings�55,69,90 For example, one study reports that 19.2% of tested individuals in four flooded villages had serological evidence of active leptospirosis following a cyclone in Orissa, india (1999)�91 A significant outbreak was seen in Taiwan following Typhoon Nali (2001)90 and, more recently, speculative evidence has emerged of an epidemic following consecutive events in the philippines in 2009�69 There are no reports of leptospirosis outbreaks in developed settings�

Other infections

The review by Shultz et al revealed that a variety of other communicable disease outbreaks have been documented, including balantidiasis and ty-phoid�1,55 These have not been reported in more recent literature�

Of note, some infections associated with other natural disasters have not been demonstrated to follow tropical cyclones� These include tetanus, hepa-titis A and hepatitis E, which have been reported in the wake of tsunamis and inland flooding.92 Their absence in the cyclone literature may represent publication bias� There are no recent reports on the impact on tuberculosis, except from one post-Katrina study which demonstrated no adverse conse-quences despite a short period of treatment program closure�93

Although there is a theoretical risk of mould-associated infections following water inundation, there is little data to suggest that this risk has ever been realised to a significant degree. Presentations of chromoblastomycosis were noted following Hurricane ike94 and mould was included amongst a list of environmental exposures thought to be associated with increased Ari post Katrina�72 This link has been questioned, however�95

In another study following Hurricane Katrina, homes with greater flood dam-age demonstrated higher levels of mould growth compared with homes with little or no flooding; however, no increase in the occurrence of adverse health outcomes was observed�96 in one paediatric sample, there was an overall decrease in mould exposure and respiratory symptoms following the event�97

Following Typhoon Morakot in southern Taiwan (2009), Hsu et al found in-creased Aspergillus spp� in both indoor and outdoor environments in the immediate wake of the cyclone�98

Non-communicable disease

More is being published about the impact of tropical cyclones on non-com-municable disease (NCd) in terms of chronic illness, acute exacerbations


and new diagnoses� This is in keeping with a trend towards increased em-phasis on NCd in the broader disaster and public health literature�

The significant, overall impact of tropical cyclones on NCD has recently been illustrated by a retrospective study that sought to quantify the number of direct and indirect deaths resulting from hurricanes Charley, Frances, ivan and Jeanne in Florida, 2004� There was an elevated mortality for up to two months following each hurricane, resulting in a total of 624 direct and in-direct deaths. In contrast, the official count was 31 direct and 113 indirect deaths resulting from the four hurricanes combined� indirect mortality ac-counted for most deaths, and was primarily due to heart disease (34%) and cancer (19%). Diabetes (5%) and accident-related deaths (9%) accounted for a smaller but not insignificant percentage of the elevated mortality.99

The elevated mortality were deaths that would not have otherwise occurred within that hurricane season�

Pre-existing illness

In developed settings, pre-existing illness accounts for a significant propor-tion of health care visits in the aftermath of events; following hurricanes Andrew and Katrina, greater than 33% of presentations were for chronic dis-ease�20,100,101 in the case of the latter, the majority of visits were for endocrine, cardiovascular, and psychiatric disorders�102 Evacuees were noted to have a high burden of disease and most medications dispensed to displaced per-sons were for chronic conditions�103-105

Cyclones have the potential to directly precipitate exacerbations of pre-ex-isting illness as well as disrupt treatment regimes� A preliminary report of mortality associated with Hurricane Charley suggested that at least six of the atraumatic deaths were the direct result of exacerbated cardiac or respi-ratory conditions�106 Surveys conducted following Hurricane Katrina found that 20.6% of survivors with chronic disease cut back or terminated their treatment because of the event. Disruptions in treatment were significantly more common among the non-elderly, uninsured, socially isolated, those with housing needs and for conditions remaining relatively asymptomatic but still dangerous if untreated� disruptions were frequently the result of problems accessing doctors and medications�107 This data is congruent with the profound disruption to primary and secondary health services that fol-lowed Katrina,108,109 which included the closure of 94 dialysis facilities along the gulf Coast110,111 and the interruption of specialist HiV/AidS clinics�81

There is emerging evidence regarding the impact of treatment disruptions following cyclones� For instance, Katrina led to an increase in HbAiC for sub-sections of the cyclone-affected community with diabetes112 and negatively impacted on the provision of chronic pain management�113 Among patients requiring haemodialysis, 44% of patients reported missing at least one ses-sion and almost 17% reported missing three or more. The adjusted odds ratio of hospitalisation among the latter group compared to those who did not miss any dialysis sessions was 2�16�114

Until recently, there has been limited data in support of a direct link between mortality and cyclone-related disruptions to public health services� While deaths due to exacerbations of chronic disease have previously been attrib-uted to cyclone events, there has been a lack of clarity about the causative factors�29,99,102,106 The significant number of deaths among hospitalised and chronically ill patients following Hurricane Katrina has helped quantify the impact of health system disruption�29

Peri-natal issues

A 2009 literature review found that, following Katrina, obstetric, prenatal, and neonatal care were compromised, but increases in adverse birth out-comes (such as preterm delivery, low birth-weight and maternal complica-tions) were mostly limited to women seriously impacted by the cyclone� They concluded that, with a few specific exceptions, post-disaster concerns and health outcomes for pregnant and postpartum women were similar to those of other people exposed to the event�115

Other studies have also failed to identify a persisting negative impact on infant and child mortality from Hurricane Katrina,116 despite speculation to the contrary�117 routine screening of newborns was, however, temporarily

interrupted by the event�118 One small study has identified an increase in con-genital cleft palate pathology. Goenjian et al report a statistically significant increase in the cases beginning 9 months after the cyclone�119 An environ-mental cause has been hypothesised�

Hurricane Katrina may have impacted on birth rates� The total number of births in selected hurricane-effected counties decreased 19 percent in the 12 months after Hurricane Katrina compared with the 12 months before�120

The decrease was not consistent across all areas however, which may reflect population shifts�115

Ischaemic heart disease

Although increased rates of ischaemic heart disease have been associated with other natural disasters,121 only recently has data emerged specifically linking acute myocardial infarction (AMi) and tropical cyclones� A single-cen-tre retrospective cohort study following Hurricane Katrina found a three-fold increased incidence in AMi after the event� in the two years post-cyclone, there were 246 admissions for AMI (2.18% of all presentations) compared with 150 admissions (0.71%) prior to the event.122 The authors suggest that changes in caseload, patient demographics and health service availability only partly account for this significant discrepancy. It has been hypothesised that AMi may be a manifestation of chronic stress121-123 but increased to-bacco use and medical non-compliance may also contribute�123 At a different institution, there was no impact on cardiothoracic operative mortality despite a significant increase in demand.124

Cancer

Recent analysis has confirmed that a significant number of patients recently diagnosed with cancer were potentially displaced following Hurricane Ka-trina�125 decreased access to care led to delayed presentations and treatment of patients with head and neck malignancies, but the clinical significance of this finding is unknown.126

Other conditions

A significant increase in alcohol use and binge drinking was observed fol-lowing Hurricane Katrina� This correlated with the number of exposures to hurricane-related traumatic events�127 in a cohort of evacuees, females and younger persons were found to be at increased risk of excess alcohol and to-bacco use�128 in the wake of Hurricane rita, alcohol use was seen to increase among a small group of adolescents displaying symptoms of post-traumatic stress�129

preliminary data from New Orleans also suggests that hurricanes Katrina and rita may have altered the redistribution of certain environmental contami-nants (including lead), potentially leading to an exposure risk for children in highly-contaminated areas�130-132

Conclusion

Cyclones are severe weather events that occur relatively frequently in tropical regions� They disproportionately affect developing countries and have the potential to cause serious disruption to basic societal functions� given the ongoing threat of tropical cyclones in northern Australia and the Asia-Pacific region, there is value in identifying their potential impacts on health�

This review was designed to expand on previous analyses by focussing on more recent literature, most of which has been generated in the US following Hurricane Katrina� The expanded volume of literature has provided a much more detailed picture of the health impact of tropical cyclones, particularly in relation to developed countries. It has also confirmed that there is a large degree of variability in the causes of morbidity and mortality between events and settings�

Trauma remains a significant cause of both, although mechanisms vary between events� Both drowning and building collapse can lead to large numbers of fatalities� Minor injuries represent the primary cause of mor-bidity in the post-impact phase but carbon monoxide poisoning from inap-propriate generator use is emerging as an important risk in both adult and paediatric patients� While communicable disease outbreaks are uncommon in developed settings, gastroenteritis, vector-borne disease and Ari pose


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Corresponding Authordr Rd Mitchell department of Emergency Medicine, Townsville Hospital, Townsville, Queensland, Australia�

Email: rob_mitchell@health�qld�gov�au

REVIEw ARTICLE

Vitamin A, Zinc, iron and iodine interventions in Children under Five Years of AgeBenjamin Wood

Sir Charles Gairdner Hospital, Perth, Western Australia; School of Public Health, Tropical Medicine and Rehabilitation Sciences, James Cook University, Townsville, Queensland

ABSTRACT

Background: micronutrient deficiency accounts for approximately 10% of all deaths and disability adjusted life years in children under the age of five. Vitamin A, iron, zinc and iodine are considered the most important of the micronutrients and have massive global health implications for this demo-graphic�

Methods: major strategies for vitamin A, zinc, iron and iodine interventions including education and dietary diversification, supplementation, fortification and integrated approaches, were reviewed�

Conclusion: vitamin A and zinc supplementation programs remain the most cost effective of all health interventions as judged by the Copenhagen con-sensus panel. Salt iodisation is the best example of micronutrient fortifica-tion to date, and is an excellent example of how political will, effective mar-

114� Anderson AH, Cohen AJ, Kutner Ng, Kopp JB, Kimmel pL, Muntner p� Missed dialysis sessions and hospital-ization in hemodialysis patients after Hurricane Katrina� Kidney int 2009;75:1202-8�

115� Harville EW, Xiong X, Buekens p� Hurricane Katrina and perinatal health� Birth 2009;36:325-31�116� Kanter rK� Child mortality after Hurricane Katrina� disaster Med public Health prep 2010;4:62-5�117� Callaghan WM, rasmussen SA, Jamieson dJ, et al� Health concerns of women and infants in times of natural

disasters: lessons learned from Hurricane Katrina� Matern Child Health J 2007;11:307-11�118� Lobato MN, yanni E, Hagar A, et al� impact of Hurricane Katrina on newborn screening in Louisiana� pediatrics

2007;120:e749-55�119� goenjian HA, Chiu ES, Alexander ME, St Hilaire H, Moses M� incidence of cleft pathology in greater New

Orleans before and after Hurricane Katrina� Cleft palate Craniofac J 2011;48:757-61�120� Hamilton BE, Sutton pd, Mathews TJ, Martin JA, Ventura SJ� The effect of Hurricane Katrina: births in the U�S�

gulf Coast region, before and after the storm� Natl Vital Stat rep 2009;58:1-28, 32�121� Bhattacharyya Mr, Steptoe A� Emotional triggers of acute coronary syndromes: strength of evidence, biologi-

cal processes, and clinical implications� progress in Cardiovascular diseases;49:353-65�122� gautam S, Menachem J, Srivastav SK, delafontaine p, irimpen A� Effect of Hurricane Katrina on the incidence

of acute coronary syndrome at a primary angioplasty center in New Orleans� disaster Med public Health prep 2009;3:144-50�

123� Jiao Z, Kakoulides SV, Moscona J, et al� Effect of Hurricane Katrina on incidence of acute myocardial infarction in New Orleans three years after the storm� Am J Cardiol 2012;109:502-5�

124� Bakaeen Fg, Huh J, Chu d, et al� Hurricane Katrina: impact on cardiac surgery case volume and outcomes� Tex Heart inst J 2008;35:273-8�

125� Joseph dA, Wingo pA, King JB, et al� Use of state cancer surveillance data to estimate the cancer burden in disaster-affected areas - Hurricane Katrina, 2005� prehosp disaster Med 2007;22:282-90�

126� Loehn B, pou AM, Nuss dW, et al� Factors affecting access to head and neck cancer care after a natural disaster: a post-Hurricane Katrina survey� Head Neck 2011;33:37-44�

127� Cerda M, Tracy M, galea S� A prospective population based study of changes in alcohol use and binge drinking after a mass traumatic event� drug Alcohol depend 2011;115:1-8�

128� Cepeda A, Valdez A, Kaplan C, Hill LE� patterns of substance use among hurricane Katrina evacuees in Hous-ton, Texas� disasters 2010;34:426-46�

129� rohrbach LA, grana r, Vernberg E, Sussman S, Sun p� impact of hurricane rita on adolescent substance use� psychiatry 2009;72:222-37�

130� Abel MT, Cobb gp, presley SM, et al� Lead distributions and risks in New Orleans following Hurricanes Katrina and rita� Environ Toxicol Chem 2010;29:1429-37�

131� Abel MT, Suedel B, presley SM, et al� Spatial distribution of lead concentrations in urban surface soils of New Orleans, Louisiana USA� Environ geochem Health 2010;32:379-89�

132� Shi H, Witt EC, 3rd, Shu S, Su T, Wang J, Adams C� Toxic trace element assessment for soils/sediments deposited during Hurricanes Katrina and rita from southern Louisiana, USA: a sequential extraction analysis� Environ Toxicol Chem 2010;29:1419-28�

keting and sound science can dramatically improve the health of a targeted population� There are still areas for improvement though with regards to micronutrient interventions, and it is important that new strategies are uti-lised appropriately� Further research is needed with regards to iron supple-mentation in malaria hyper-endemic regions�

Keywords: micronutrients, vitamin A, iron, zinc, iodine, deficiencies, chil-dren, supplementation, fortification


BackgroundMalnutrition is estimated to account for 11% of the global burden of dis-ease�1 Malnutrition can be divided into two major categories: protein-energy malnutrition and micronutrient deficiencies.2 These two areas of nutrition deficiencies are interconnected and very often simultaneously exist. They are both complexly intertwined with geographical, socio-economic and po-litical influences. The scope of this literature review will focus on four major micronutrient deficiencies with major global health implications for children – vitamin A, zinc, iodine and iron�

It is estimated that micronutrient deficiencies affect at least 2 billion people worldwide. In children less than five years of age, micronutrient deficiencies account for approximately 10% of deaths and disability-adjusted life years.3 Much of this burden stems from deficiencies in vitamin A and zinc.3 Deficien-cies in vitamin A, zinc, iodine and iron are undoubtedly massive global health concerns that predominately affect developing countries� Adequate provi-sion of these important micronutrients is vital to ensure appropriate physical, mental and cognitive development, and long-term health�4


roughly 250 million people, mainly pregnant women and young children, are affected by vitamin A deficiency (VAD).5 Vitamin A is important for the immune system and it is vital for the physical health of children exposed to illnesses�2 VAd dramatically increases the risk and mortality from typical childhood infections such as diarrhoeal disease�5 Vitamin A is also integral to the functioning of a healthy eye, being vital to the retina’s ability to adjust to dark lighting, and to the protection of the cornea from scarring�4 VAd results in a condition called xerophthalmia, a disorder which is the leading cause of preventable blindness in children� An estimated 250 000 to 500 000 children who are vitamin A deficient become blind annually. Half of these children die within a year of becoming blind�5

About 2 billion people worldwide are zinc deficient.2 Zinc is essential for promoting immunity, resisting infections, and for promoting the production of antibodies against gut pathogens� Zinc supplementation, alongside oral rehydration therapy, reduces diarrhoeal rates in children by 27%. Consider-ing 18% of deaths under the age of five are attributed to diarrhoea, this is a major finding. Zinc supplementation can also lower the rates of acute lower respiratory infections by 15%,6 and reduces the rates of malaria�7 Zinc is also important for the growth and development of the nervous system�4

iron is vital for human development and functioning�4 Iron deficiency is the most common nutritional deficiency globally and affects both developing and developed nations�2 it is the major cause of anaemia worldwide, and increases the mortality and morbidity in children. It is estimated that 40% of preschool children are anaemic�8 Communicable diseases such as worm infections, malaria, HIV and TB aggravate iron deficiency anaemia, making it a major issue in many developing nations�7 Iron deficiency is also a common cause of psychomotor disorders and cognitive impairment, and has been shown to decrease the level of physical activity undertaken�4

iodine is critical element required for nervous system development�4 iodine deficiency is the most common cause of brain damage worldwide, yet it is easily preventable�9 Iodine deficiency is a significant public health issue in 130 countries, with about 750 million people affected�10 in those communi-ties where iodine intake is sufficient, the average IQ, on average, has been shown to be about 13 points higher than those where intake is insufficient.11

ObjectivesThe objectives of this review are to highlight the global health significance of the four major micronutrient deficiencies focusing on their impact on the morbidity and mortality of children, review public health interventions that aim to address these deficiencies, and to review what needs to be done with future efforts�

MethodspubMed, google Scholar and the WHO database were used as search en-gines for this review using the following keywords: micronutrients, iron, zinc, vitamin A, iodine, deficiencies, children, public health interventions.

discussionMany programs addressing micronutrient deficiencies have yielded proven success in improving physical and cognitive capacity� The excellent cost-effectiveness of micronutrient interventions have received many accolades, and in 2008, vitamin A and zinc supplementation for children was stated by the Copenhagen consensus panel, out of all global development efforts, to provide the very best return on investment. Iron and iodine food fortification was also ranked third on the list�11

Education and dietary diversificationEducation directed towards populations at micronutrient deficiency risk is clearly important in any intervention program� These programs mainly look at the importance of dietary diversification of foods containing important micronutrients. One study has found that education and dietary diversifica-tion slightly improved haemoglobin levels from 102 to 107g/L,3 with another showing it slightly improved vitamin A�3 recent literature supports improve-ment of dietary zinc through the production and consumption of animal source foods�12 However, there is limited documentation of the impact of

education and information alone�13 An advantage of educational programs is that they are sustainable, and if delivered effectively, promote long-lasting behaviour change in a population�13 There is evidence that these programs that specifically target education can work in relatively advantaged popula-tions�14 However, there are several drawbacks to education programs alone� it is important to realise that changes in behaviour and practices will be con-fined to the socio-economic and geographical capabilities of the targeted population�13 The take-home message of many nutritional reviews is that education and dietary diversification is important in all nutritional interven-tions� However, it should not be used as a stand-alone technique, but in combination with other proven techniques that will be mentioned�

SupplementationMicronutrient supplementation of targeted populations of young children has been proven to be very cost-effective, particularly for vitamin A and zinc� Supplementation is usually delivered through primary healthcare systems, and commonly coupled with immunisation programs�13 Supplementation programs are only effective if the supplements reach a high percentage of people in the vulnerable population, and if the delivery system has built-in quality control�13

Vitamin A supplementationVitamin A (VA) supplementation is undoubtedly one of the most effective child survival interventions�4 Systematic review of rCTs showed that one dose of VA reduced the mortality risk of children aged between 6 months and 5 years by 12%, with two doses reducing the risk by 22%.3 Studies in Asia showed that neonatal supplementation reduced mortality of children between the age of 2 days and 6 months by 21%.3 VA was also shown to reduce the burden of multiple diseases, including persistent diarrhoea with a rate ratio of 0�45�3 it was estimated that nearly two-thirds of children in developing countries under the age of five received two high-dose VA sup-plements�15 What is even more impressive is that 82% of children under the age of five in the least developed countries of the world received coverage, highlighting what happens when political will and international resources are available�7 VA supplementation has also been shown in studies to improve the efficacy of iron supplementation by increasing haemoglobin levels. This believed to be done stimulating erythroid precursors and improving the availability of iron to the bone marrow�16

Zinc supplementationin 2004, a joint statement was made by UNiCEF and WHO recommending zinc supplementation (ZS) in the management of diarrhoea�7 despite these recommendations, as of 2010, only 46 countries utilised a zinc policy in their child health delivery�7 Four systematic reviews have shown that preventive ZS in children greater than 6 months was shown to reduce the overall mor-tality risk by 9%, and reduce the odds of stunting by 15%.3 A meta-analysis revealed that ZS reduces the duration of diarrhoea by 15-24%,3,17,18 reduced the episodes of diarrhoea and dysentery3 and the frequency of lower respira-tory infections by 15-24%.17

iron supplementationStudies have shown that iron supplementation (irS) resulted in a haemo-globin concentration increase of 7�4 g/L�19 irS alone reduced the occurrence of anaemia in regions not endemic for malaria from 6-32%.16 However, it is important to note that potentially there is an increased risk of childhood mortality in hyper-endemic malarial regions� This recommendation was brought about by a trial in Tanzania which showed there was an increase in mortality in children receiving irS, and hence the trial was stopped prema-turely�20 Several other studies have also showed a correlation between irS and communicable diseases, although further research is needed to make this conclusive�21

iodine supplementationiodine supplementation is generally reserved for pregnant women� iodine fortification is the leading intervention for targeting children populations which are iodine deficient.


FortificationFood fortification with micronutrients is a constantly evolving public health intervention. Fortification can be broken down into two general approaches – central and peripheral fortification.13 Central fortification involves adding micronutrients to foods in a centralised manner prior to distribution or mar-keting�13 Peripheral fortification involves adding micronutrients to food in the household�13 The great advantage of central fortification done in a safe manner is that minimal behavioural change or motivation is necessary in the population to instigate health benefits. This approach does require sound scientific evidence, political will and leadership and effective implementation. Also, ensuring equal coverage is paramount, with rural populations often neglected in such interventions. Peripheral fortification can be utilised to target certain vulnerable sub-groups such as young children� This approach requires active participation form household leaders�13

Vitamin A fortificationThere have been interventions of VA fortification to foods such as cooking oils, monosodium glutamate (MSg) and sugar�6 Evidence for the effective-ness of fortification of these foods with VA is difficult to find, however a study showed a 30% mortality reduction in children aged 6 months – 5 years in a population in Indonesia given commercially fortified MSG.22

Zinc fortificationWHO recommends zinc as a curative measure only for childhood illnesses and diarrhoea,23 and there is minimal data to support central zinc fortifica-tion�24 As a result, there is limited data on zinc fortification strategies. A study in Senegal showed food containing zinc-fortification did not increase plasma zinc concentration, unlike ZS for 15 days which did�25 A study in northern India where children were given fortified milk with multiple nutri-ents, including zinc and iron, had an 18% lower incidence of diarrhoea and a 26% lower incidence of pneumonia.26

iron fortificationThere has been much debate about the efficacy of iron fortification. Similar to irS, there is unclear data about whether this intervention is safe for chil-dren in malaria hyper-endemic regions. Iron fortification has been shown to reduce the rate of anaemia by more than two-thirds in school children in Chile�27,28 It has been estimated that iron fortification of staple foods could potentially prevent 8% of DALYs of children – a massive 123 000 DALYs.3 A study in India where food was fortified with iron and riboflavin showed a reduction in the prevalence of anaemia by more than half�13 More research, however, needs to be done in hyper-endemic malarial regions before wide-spread interventions can be made with sound scientific backing.

iodine fortificationUndoubtedly the greatest success in food fortification has been with the iodisation of salt� This is a fantastic global health example of how good governance and market opportunity can improve the health of a population�4 Salt iodisation is estimated to reduce DALYs from iodine deficiency by 41% in children�3 Less than one in five developing world households were using iodised salt in 1990. In 2010, this number increased to 70%, with more than 30 developing countries reaching the universal iodised salt goal�4 Having said this, 24 countries in 2010 showed no growth and even decline in iodised salt coverage. In half of these countries, one in five is consuming adequate iodised salt levels�4 iodised water has been shown to reduce infant mortality by more than a half in studied areas,16 and neonatal mortality by nearly two thirds�16

integrated approachesintegrated approaches include child nutrition programs, the Essential Nutri-tion Actions approach and conditional cash transfers�

Child nutrition through child health programsChild health weeks (CHWs) are an excellent example of delivering a range of services for child health through an existing health system� This requires a sound and effective public health structure with appropriate evaluation and

monitoring�4 Let us take a look at Zambia, which in 2000 with the assis-tance of UNiCEF, has been implementing half-annual CHWs� Here, alongside routine vaccinations, deworming, malaria prevention strategies and growth monitoring, vitamin A supplements are given� Evaluation performed in 2003 showed that through these CHWs, 77% of children received VA. This was shown to halve the level of VA deficiency, with anaemia being reduced by 12%.4

The Essential Nutrition Actions (ENA) approachThe ENA approach evolved from the Lancet Child Survival series which re-ported a set of nutritional interventions that were shown to reduce childhood mortality�29 it was developed by WHO, UNiCEF and the US Agency for inter-national Development and includes a focus on the first two years of child-hood�13 Vitamin A, zinc supplementation and exclusive breastfeeding in the first 6 months of life are strategies in the ENA framework.13 This integrated approach has been shown to be effective in numerous developing countries, with an example being Madagascar�13

Conditional cash transfers (CCTs)CCTs have become widespread in Latin America, and are based on financial payments to poor and vulnerable populations in exchange for completing certain conditions� These conditions include a certain school attendance rate for children, use of primary healthcare services and nutrition programs�13

perhaps the most successful of the CCT programs has been in Mexico, which includes food fortification and micronutrient supplementation of chil-dren aged between 6 months and 2 years� The effect on anaemia prevalence and infant growth has been markedly positive since the commencement of this program�30

What needs to be doneNational governments and development partners need to increase long-term investment to yield greater and further returns�11 More affordable, feasi-ble and evidence-based programs are emerging, and should be utilised to expand the potential benefits of addressing these major micronutrient defi-ciencies�11 Monitoring and surveillance of nutritional programs is paramount for the success of current and future interventions� This includes popula-tion monitoring assessing change in dietary behaviours which will guide alterations of programs, allowing them to be more efficient and effective. resources need to be mobilised in national budgets so that each country can sustain appropriate nutritional interventions on a long term basis� The me-dia, including social media, should be utilised for awareness, motivation and mobilisation of the masses, and should be incorporated into national health systems and schools�4 The 2009 Global Report on micronutrient deficiencies sets the coverage target of those receiving twice-yearly VA supplementation on a repeated basis as greater than 80%.4 The other ‘difficult-to-reach’ 20% who are missed in regular programs will need to be targeted with special, context-specific programs such as integrated outreach programs.4 Manda-tory legislation of salt iodisation, with appropriate enforcement capabilities, should be made� incentives should be made to salt processors in developing countries to ensure they iodise their salt, with a transition from a donor-dependent to a market-supported supply important for sustainability�4 Zinc supplementation needs to be implemented into each nation’s policy for the management of diarrhoea in children�4 This will involve ensuring an adequate zinc supply, with appropriate delivery strategies� Safe strategies to improve iron intake need to be made clear for policy makers and program designers� Further directed research needs to be done with regards to iron supplemen-tation in hyper-endemic malaria regions�4

ConclusionMicronutrient deficiencies, especially that of vitamin A, zinc, iron and iodine, result in an enormous health burden on children under the age of five. Over the last few decades, there have been a large number of programs designed to target this issue� Some of these programs have been touted as being some of the most cost-effective health programs that exist today� Sup-plementation programs with zinc and vitamin A have produced staggering results in terms of the reduction of childhood mortality and morbidity� How-


ever, these programs need to be scaled up to ensure coverage is expanded and performed on a recurrent basis� Coverage needs to include targeting the neglected groups of a population that have been missed with other routine programs. Nutritional intervention is an evolving field, with food fortifica-tion strategies emerging as an area of great potential� Further research and data is needed however with food fortification strategies, and governments need to ensure they maintain the political will to ensure up-to-date legislative changes that promote better nutritional health�

References1� World Health Assembly� Maternal, infant and young child nutrition� Sixty-Fifth World Health Assembly� WHO�

2012;13(3):1-2�

2� Muller O, Krawinkel M� Malnutrition and health in developing countries� CMAJ� 2005;173(3):279-285�

3� Bhutta Z, Ahmad T, Black rE, et al� What works? interventions for maternal and child undernutrition and survival� Lancet 2008;10(1):41-46�

4. The Micronutrient Initiative. Investing in the Future: A United Call to Action on Vitamin and Mineral Deficien-cies. 2009. Available from: http://www.unitedcalltoaction.org/flashreport.asp (accessed May 3 2013).

5. World Health Organization. Programmes: Nutrition. Vitamin A deficiency. Geneva: WHO, 2013. Available from: http://www�who�int/nutrition/topics/vad/en/index�html (accessed May 5 2013�)

6� World Health Organization� Comprehensive implementation plan on maternal, infant and young child nutrition� 2012;A65(11):1-14�

7. Khan Y, Bhutta ZA. Nutritional deficiencies in the developing world: current status and opportunities for inter-vention� pediatr Clin North Am 2010;57:1409-1441�

8. World Health Organization. Programmes: Nutrition. Iron deficiency anaemia . Geneva: WHO, 2013. Available from: http://www�who�int/nutrition/topics/ida/en/index�html (acessed May 6 2013�)

9. World Health Organization. Programmes: Nutrition. Iodine deficiency disorders. Geneva: WHO, 2013. Avail-able from: http://www�who�int/nutrition/topics/idd/en/index�html (accessed May 6 2013)�

10. Prinzo Z, De Benoist B. Meeting the challenges of micronutrient deficiencies in emergency-affected popula-tions� department of Nutrition for Health and development, WHO� 2002;61:251-257�

11� Food and Agriculture Organization of the United Nations� Undernourishment around the world� The state of food insecurity in the world� rome: FAO, 2004�

12. Gibson R, Anderson V. A review of interventions based on dietary diversification or modification strategies with the potential to enhance intakes of total and absorbable zinc� Food Nutr Bull 2009;30 (1):108-43�

13. Harrison G. Public Health Interventions to Combat Micronutrient Deficiencies. Publ Hlth Rev 2010 Jul;32(1):256-266�

14� Contento i, Balch gi, Bronner yL, et al� The effectiveness of nutrition education and implications for nutrition education policy, programs and research: a review of research� J Nutr Educ 1995;27:279-83�

15� Bhutta Z� Micronutrient needs of malnourished children� Curr Opin Clin Nutr Metab Care 2008;11:309-14�

16. Khan Y, Bhutta ZA. Nutritional deficiencies in the developing world: current status and opportunities for inter-vention� pediatr Clin North Am 2010;57:1409-1441�

Corresponding Authordr Benjamin Wood Sir Charles gairdner Hospital, perth, Western Australia; School of public Health, Tropical Medicine and rehabilitation Sci-ences, James Cook University, Townsville, Queensland

Email: benjaminmwood88@gmail�com

REVIEw ARTICLE

Hearing loss in MalariaEric Fong

School of Public Health and Tropical Medicine, James Cook University, Townsville

ABSTRACT

Background: Malaria is a preventable and treatable infectious disease; how-ever, malaria is extremely common in many parts of the world� Hearing loss can be devastating and adversely affect individuals and populations� Ma-laria and antimalarial regimens may affect hearing, thus causing significant functional, social, and developmental issues� This article explores the link between hearing loss and malaria, and ototoxicity from antimalarial chemo-therapy�

Aim: The aim of this study was to perform a systematic literature review on hearing loss in malaria�

design: A systematic search of the literature and a discussion of the results�

Method: A search was performed in MEdLiNE via OvidSp, Scopus, and pubMed databases�

results: Of 13 papers analysed, one was a systematic review on the direct effect of malaria on hearing loss, which suggested that malaria may directly

17� Sazawal S, Black rE, ramsan M, et al� Effect of zinc supplementation on mortality in children aged 1–48 months: a community-based randomised placebo-controlled trial� Lancet 2007;369:927-34�

18� Tielsch J, Khatry S, Stoltzfus r, et al� Effect of routine prophylactic supplementation with iron and folic acid on preschool child mortality in southern Nepal: community-based, cluster-randomised, placebo-controlled trial� Lancet 2006;367: 144–52�

19� gera T, Sachdev Hp, Nestel p, et al� Effect of iron supplementation on haemoglobin response in children: systematic review of randomised controlled trials� J pediatr gastroenterol Nutr 2007;44:468–86�

20� Sazawal S, Black r, ramsan M, et al� Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial� Lancet 2006;367:133-43�

21. Iannotti L, Tielsch J, Black M, et al. Iron supplementation in early childhood: health benefits and risks. Am J Clin Nutr 2006;84:1261-76�

22. Muhilal, Permeisih D, Idjradinata YR, et al. Vitamin A-fortified monosodium glutamate and health, growth, and survival of children: a controlled field trial. Am J Clin Nutr 1988;48:1271-76.

23� World Health Organization, UNiCEF� Joint statement on the management of acute diarrhoea� geneva: WHO, 2004� p13�

24. Salgueiro M, Zubigalla M, Lysioek A, et al. Fortification strategies to combat zinc and iron deficiency. Nutr Rev 2002;60:52-8�

25� Ba Lo N, Aaron gJ, Hess Sy, et al� plasma zinc concentration responds to short-term zinc supplementation, but not zinc fortification, in young children in Senegal. Am J Clin Nutr 2011;93(6):1348-55.

26. Sazawal S, Dhingra U, Dhingra P, et al. Effects of fortified milk on morbidity in young children in north India: community based, randomised, double masked placebo controlled trial� Br Med J 2007;334:140�

27. Nadiger H, Krishnamachari K, Naidu A, et al. The use of common salt (sodium chloride) fortified with iron to control anaemia: results of a preliminary study� Br J Nutr 1980;43:45-51�

28. Walter T, Hertrampf E, Pizarro F, et al. Effect of bovine-hemoglobin-fortified cookies on iron status of school-children: a nationwide program in Chile� Am J Clin Nutr 1993;57:190-4�

29� Jones g, Steketee r, Black r, Buttha Z, et al� How many child deaths can we prevent this year? Lancet 2003;362:65-71�

30� rivera J, Sotres-Alvarez d, Habicht J, et al� impact of the Mexican program for education, health and nutrition (progresa) on rates of growth and anemia in infants and young children: a randomized effectiveness study� JAMA 2004;291:2563-70�

cause hearing loss through biological processes not well understood� No prospective studies on this issue have been done to date� Collectively, re-ports have shown minimal evidence that antimalarial medications cause oto-toxicity, except for quinine, which is well recognised as an ototoxic agent�

Conclusion: This study highlights evidence that malaria may cause hearing impairment. Although there is limited definitive evidence, the impact malaria may have on altering hearing thresholds is increasingly recognised� Most antimalarial medications are safe for the ear� Quinine produces a predictable, but reversible, hearing loss� More research should aim to identify whether a direct link exists between malaria and hearing loss because malaria is a global burden, the impact of hearing loss can be substantial, and studies evaluating drug toxicity may be confounded by deafness due to malaria itself�

Keywords: malaria, hearing loss, ototoxicity, antimalarials, chemotherapy


introductionimpact of malaria

Malaria is a disease of poverty that affects hundreds of millions of people worldwide, with many more at risk of exposure�1 Malaria can cause neuro-cognitive disorders, and it is well recognised that Plasmodium falciparum causes language disorders in children, although the mechanism is unclear�2 Hearing is a component of language and is known to be affected by some antimalarial agents�3 Although ototoxicity studies have been done to evaluate these drugs, most studies assume that the affected individual has normal hearing, since audiometric testing is usually done during and after treatment


for acute malaria�4,5 Therefore, malaria and antimalarial agents may alter hearing thresholds causing deafness and ultimately impairing language� The impact of deafness on the individual and the population includes functional, social, and economic aspects, both in the child and adult, so exploring this proposed association may help identify new avenues for preventing hearing loss�6 This review of the current literature was undertaken to investigate whether malaria and antimalarial treatment regimens cause hearing prob-lems, as the use of these drugs for febrile illness is widespread�3

Malaria disease

Malaria is a parasitic infection that affected 216 million people in 2010 with 3�3 billion people at risk�1 young children are at increased risk of malaria because immunity to malaria has not yet developed, and as a result young children living in endemic areas of malaria are a particular population at risk�1 given that childhood development is sensitive to environmental in-sults, malaria can adversely affect normal growth�1 Deficiencies in areas such as language can occur due to restricted brain development�2 This can restrict learning, social interaction, and functional capacity to work, which has serious effects not only for the affected individual but at the social and economic level�6 These impairments are associated with a significant bur-den, especially in those affected in sub-Saharan Africa, which has high levels of malaria transmission�7

Chemotherapy agents used for malaria treatment may also be involved in damaging the brain and, in particular, hearing function� These agents can be toxic enough to be harmful to sensitive organs such as the inner ear�8 For example, artemether-lumefantrine is an effective antimalarial for uncom-plicated Plasmodium falciparum�9 dose-response relationships have been established for artemisinin derivatives and toxicity on brain areas involved in hearing in animal studies�3,10,11 in stable malaria transmission situations, qui-nine is commonly used as a first-line agent in children with a febrile illness for presumed malaria, and can exert neurotoxic effects, as demonstrated in the laboratory�3 Mefloquine is mainly a chemoprophylactic agent, but its side effect profile includes neuropsychiatric disorders that have been linked to toxicity in the brain� The evidence that these agents may be involved in ototoxicity and significant hearing loss in humans will be reviewed.

Hearing loss

Hearing loss is a well-recognised global issue that affects around 278 mil-lion people in the world�12 In developing countries, 50% of hearing loss has been estimated to be preventable� Many cases in the developing world may have no explanation as to the cause of deafness�12 Although there are numerous aetiologies for hearing loss, malaria or its treatment regimens may help explain cases of unknown origin, and clarifying its role in hearing impairment may allow public health strategies to be put into practice to avoid a potentially preventable cause of deafness�12 Cerebral malaria, which is a complication of severe malaria, may cause persisting neurological issues, including deafness�13 However, many individuals do not experience cerebral malaria and yet unexplained deafness is common in malaria-endemic areas�4 Malaria may explain this large proportion of preventable cases of deafness�

The effect of deafness on paediatric populations has been studied and evi-dence suggests that deafness in children may result in poor attention span, leading to limited class participation and hindering the learning experience, restricting their potential�6,14 An association between malaria parasite den-sity and level of concentration of schoolchildren, showing a dose-response relationship, has been suggested in a number of studies�15-18 The cause of this cognitive decline is unclear and is likely due to anaemia and brain hy-poxia,15-18 but hearing loss has been suggested to be a plausible explana-tion�4 This can have serious consequences, as the effects of hearing loss can result in functional, social, and developmental issues in the developing child and these problems may continue into adulthood�6 The deaf adult may have poor language abilities, and consequently, limited social interaction and occupational capacity�14 This translates into public health and economic is-sues to allocate resources towards screening, rehabilitation, and hearing aid programs, for an issue which may be preventable�19

MethodsTwo systematic literature searches were undertaken� A systemic literature search was performed on MEdLiNE via OvidSp, Scopus, and pubMed data-bases� The keyword ‘malaria’ was used with ‘hearing loss or ototoxicity’� A second systematic search was completed using the keywords ‘neurologi-cal or neurocognitive deficits’ and ‘malaria’ and these articles were selected based on available internal data on hearing loss� Articles were limited to English. Evidence for safety profiles of chemotherapeutic agents was limited to clinical studies�

ResultsThirteen articles were selected after analysis as meeting the inclusion criteria for this review� There were three studies looking at the direct effect of ma-laria on hearing, which include a systematic review, a clinical trial, and one laboratory report� results for studies on safety of antimalarials included four clinical trials, two case control trials, one retrospective and two prospective studies, and a case report. The findings are summarised in Tables 1 and 2 and will be discussed next�

discussiondirect effect of malaria on hearing

There are a limited number of studies that directly investigate the association between malaria and hearing loss (Table 1�) The most recent review pub-lished by Zhao and Mackenzie in 2011 analysed 14 studies and suggested an association of deafness due to the neurological deficits secondary to cerebral malaria, but could not show a strong causal relationship between uncom-plicated malaria and deafness�20 Their study found a small but significant proportion of hearing loss was associated with a non-specific fever or febrile illness in countries where the most common cause of fever is malaria�20 re-call and measurement bias in these studies, however, makes it unknown as to whether causation exists. They conclude that clinically-significant hearing impairment occurs only in severe disease, and that less-noticeable hearing deficits, which may not be recognised, may be present in uncomplicated malaria�20

Zhao and Mackenzie suggest that during a malarial infection prior to treat-ment, the level of hearing is reduced, and thus hearing may appear to be affected during the treatment period� Since baseline hearing function has been assumed to be normal in other studies, the actual amount of hearing loss is unknown and there could be potential loss due to the infection prior to treatment�20 These authors suggest that if this occurs, treatment may further damage hearing, and although hearing improves at follow-up compared to testing at pre-treatment, this might not represent the true hearing threshold as no baseline of hearing was recorded prior to parasitic infection in the stud-ies they reviewed�20 These theories are supported by work in ghana which showed that hearing thresholds differed significantly (p<0.001) between children with an acute illness of uncomplicated P. falciparum and healthy controls�21 After 9 months follow-up the study measured hearing thresholds again, and found thresholds were not significantly different among the two groups�21 This suggests if P. falciparum affects hearing, the deafness may be transient and reversible� This study has implications for research in drug therapy for ototoxicity, since evaluating ototoxicity during the period of acute illness may be confounded by the presumed ototoxic effect of malaria�21

Although clinical studies have not been performed sufficiently to establish an association, a laboratory study by Schmutzhard et al demonstrated signifi-cant hearing loss in mice following cerebral malaria�22 They concluded that malaria significantly causes hearing impairment in mice by studying auditory evoked brainstem responses (ABrs), which measures hearing thresholds, before and after infection� in addition, they demonstrated that higher hearing thresholds occurred in mice with cerebral malaria compared to uncompli-cated malaria, which suggests the severity of malaria has a more significant effect on hearing�22 There are no human studies demonstrating similar find-ings, probably because the mouse model of cerebral malaria is not directly comparable to human cerebral malaria�


Table 1 Summary of evidence suggesting the direct effects of malaria on hearing

STudY TYPE, SAMPlE SiZE METHOD OF MEASUREMENT FINDINGS AUTHOR & REFERENCE

Systematic literature review review of 14 studiesFalciparum infection may potentially lead to hearing loss

Zhao and Mackenzie20

Clinical trial artesunate- amodiaquine (n=37), artemether- lumefantrine (n=35), or amodiaquine (n=8) in children

Audiometric thresholds compared to controls

in the acute setting malaria may cause elevated hearing thresholds

Adjei et al21

Mice murine cerebral malaria

(n=20)Auditory brainstem response testing Significant hearing impairment Schmutzhard et al22

proposed mechanisms for hearing loss in malaria

Zhao and Mackenzie suggest that multiple mechanisms ultimately lead to damage of three core areas involved in hearing� These include the coch-lea, the cochlear nerve, and the brainstem and its associated structures that participate in hearing�20 indirectly, malaria may increase risk of acquiring other auditory damaging infections which can lead to hearing loss�20 Lo-cal microvascular changes of cochlear end arteries has been suggested to be the prime mechanism of contributing directly towards hearing loss and this pathological alteration may be implicated in lowering resistance to other infections�23

The lack of causation between uncomplicated malaria and hearing loss may be because any deafness suffered from uncomplicated malaria is not rec-ognised or is underreported�20 This might be compounded by the fact that the issue has not been studied in detail, according to the lack of research in the literature� The reviewed clinical studies support the need for further re-search in the area due to the considerable absence of evidence, especially in humans� prospective studies should be performed to help establish whether causation exists�

Antimalarial agents and ototoxicity

Artemisinins have been thoroughly studied due to concerns regarding neurotoxicity based on animal studies�10,11 Amodiaquine-artesunate and artemether-lumefantrine were randomised in an efficacy and safety trial in ghana, powered by 227 children aged six months to 14 years with uncom-plicated malaria�24 No significant differences in hearing were reported during the one year study, which included a monthly follow-up period� A matched case-control that involved 68 adults on artemether-lumefantrine compared with 68 matched-controls similarly did not show evidence that artemether-lumefantrine causes hearing impairment�25 Hearing loss was common in this study in both groups, but statistical analysis showed that only age was significantly associated, and was unrelated to artemether-lumefantrine expo-sure�25 These findings are supported by a randomised prospective study by Carrasquilla et al that found no significant difference in auditory brainstem response (ABr) in 265 patients randomised to artemether-lumefantrine or artesunate-mefloquine.26 One early study evaluating audiometric changes during use of artemether-lumefantrine for uncomplicated malaria was a matched case-control trial study of 300 patients�27 This study found a sig-nificant (p<0.05), albeit small, hearing impairment at frequencies of 1-8 kHz but not in the 500 to 250 Hz range� However, the samples collected were from a construction site, and there was no information provided about sam-pling and differences of noise exposure between the two groups, making conclusions drawn from this study less reliable�27 A randomised trial as-sessing artemether-lumefantrine, quinine, and atovaquone-proguanil evalu-ated hearing function with tuning fork tests, pure tone audiometry, transient evoked and distortion product otoacoustic emission, and ABr before, dur-ing, and after treatment on days 0, 7, 28, and 90�28 This comprehensive

trial demonstrated that artemether-lumefantrine does not appear to cause hearing impairment� The one case of a patient on artemether-lumefantrine with significant deafness on day 90 was attributed to malaria reinfection.28

in the same study, it was found that quinine was associated with a hearing loss of 30 dB, although this was transient�28 A significant number of patients (9 out of 30) on day 7 of quinine therapy complained of hearing issues, but all but one complaint about deafness disappeared by the day 28 visit, and no hearing problems were reported by day 90�28 Quinine is well recognised to cause toxicity to the outer hair cells of the ear, but its effect is reversible and the patients in this study did not complain of hearing issues by day 90�28 His-torically, quinine derivatives have a well-recognised ototoxic profile, as cin-chonism, a syndrome that occurs from quinine toxicity, results in headache, deafness, and anaphylactic shock�3 in Tanzania, a large number of children were suspected of having profound sensorineural deafness�29 A subsequent pilot study found 36% of deaf children had received intramuscular quinine and/or gentamicin for ‘fever’ on admission�29 This highlights the potential for ototoxicity due to the improper use and monitoring of these two drugs, as they both have ototoxic properties� A study by Flanagan et al evaluat-ing the role of measuring routine quinine levels found that hearing loss due to quinine occurs regardless of oral or parenteral route but is likely to be completely reversible�30 Quinine plasma levels do not appear to correlate well with hearing loss, and individual risk may be better assessed by hearing tests rather than measuring quinine levels�30 This is supported by an older study that produced similar results, with reversal of hearing loss within one week, according to audiograms�31 Evidence suggests that although quinine may produce deafness, it is a transient event that may completely return to normal, and that audiometric testing rather than blood tests may be done for those patients on quinine to reliably monitor its ototoxic effects�

Mefloquine might potentially affect hearing, since the side effect profile of mefloquine includes neuropsychiatric disturbances, likely due to its neuro-toxic properties�32,33 However, an open-label phase iV study of African chil-dren with uncomplicated malaria treated with three-day artesunate and me-floquine failed to demonstrate convincing evidence of hearing loss (95% CI: 0.0 to 1.73 % of patients), although this was not the direct end-point of their study�34 A prospective study of 93 patients with uncomplicated malaria on three-day mefloquine-artesunate in Thailand also could not suggest clinical evidence via audiometric and ABr testing�35 This study tested ABr on day 0 and day 7, and did not find evidence to suggest artesunate or mefloquine are toxic to the auditory system�35 One Canadian case report concerned a 67-year-old woman who had mefloquine chemoprophylaxis and developed unilateral sudden profound sensorineural hearing loss and tinnitus, which resolved spontaneously at day 93 of her illness, but no causal interpretation could be made�36

Artemether-lumefantrine does not appear to cause hearing loss and this evidence supports its safety in this context. These clinical studies confirm


STUDy TyPE AND TOTAL SiZE STudY FACTOR, SAMPlE SiZE, ANd METHOdOlOgY FINDINGS AUTHOR &

REFERENCE

Randomised efficacy and safety trial (n=227)

random treatment of uncomplicated malaria in children 6 months to 14 years to amodiaquone-artesunate (n=116) or artemether-lumefantrine (n=111), follow-up in 28 days for reports of adverse events

rare instances of side effects and no reports of hearing impairment nor abnormal neurological signs

Adjei et al24

Case-control (n=136)

group treated with artemether-lumefantrine within 5 years (n=68) vs matched controls (n=68) compared for audiometric differences

No audiometric difference between cases and controls

Hutagalung et al25

randomised, prospective open-label three-arm study (n=265)

random assignment to artemether-lumefantrine (n=159), atovaquone-proguanil (n=53), or artesunate-mefloquine (n=53) and auditory brain response (ABr) comparison

No difference in ABr; 2-4 dB pure-tone threshold improvement

Carrasquilla et al26

Matched case-control trial (n=300)

Artemether-lumefantrine (n=150) to treat uncomplicated malaria vs age-, gender-, weight- and race-matched controls (n=150) who did not suffer malaria and did not have antimalarial therapy with comparison of audiometric findings

Subjects in the artemether-lumefantrine group had significant hearing loss compared to controls

Toovey and Jamieson27

randomised double-blinded controlled trial (n=77)

random assignment to receive artemether/lumefantrine (n=23) or quinine (n=26) or atovaquone/proguanil (n=28) and comparison of peripheral and brainstem auditory pathway assessment

No impact of standard oral dosing of artemether-lumefantrine on either peripheral or brainstem auditory pathways; transient hearing loss on day 7 with quinine therapy

gurkov et al28

retrospective audit (n=82)

Quinine plasma level results and correlation with toxicity effects

Hearing loss occurs almost invariably but may not occur in a dose-response relationship

Flanagan et al30

Experimental study (n=22)

Audiometric testing before and after doses of quinine administered in 12 healthy subjects and 10 patients with falciparum malaria

High frequency loss reversible within one week

Tange et al31

Experimental phase iV open label study (n=213)

Treatment of African children with uncomplicated P. falciparum treated over three days with artesunate-mefloquine combination with follow-up to report adverse events

No reports of hearing loss Frey et al34

prospective study (n=93)3-day oral artesunate-mefloquine in patients with uncomplicated falciparum and auditory testing before the first dose and seven days after the first dose was started

No threshold changes of significance (changes did not exceed 10 dB)

Carrara et al35

Case report Case analysis of a woman on chemoprophylactic weekly mefloquine

Sudden right ear severe sensorineural hearing loss and tinnitus with spontaneous resolution after day 93 of hearing loss

Wise and Toovey36

Table 2 Summary of studies on antimalarials and relationship with hearing function


References1� WHO� World Malaria report, 2011� geneva: World Health Organization� Available from: http://www�who�int/

malaria/world_malaria_report_2011/en/index�html (accessed 23/04/2013)

2� Carter JA, Mung’ala-Odera V, Neville Bgr, Murira g, Mturi N, Musumba C, et al� persistent neurocognitive im-pairments associated with severe falciparum malaria in Kenyan children� Journal of Neurology, Neurosurgery & psychiatry� 2005;76(4):476-481�

3� AlKadi HO� Antimalarial drug toxicity: a review� Chemotherapy� 2007;53(6):385-391�

4� Chukuezi A� Hearing loss: a possible consequence of malaria� Afr Health� 1995;17(6):18-9�

5� Smith AW� The World Health Organization and the prevention of deafness and hearing impairment caused by noise� Noise Health� 1998;1(1):6-12�

6� WHO� deafness and hearing loss� geneva: World Health Organization, 2013� Available from: http://www�who�int/mediacentre/factsheets/fs300/en/ (accessed 11/05/2013)

7� Mung’Ala-Odera V, Snow rW, Newton Cr� The burden of the neurocognitive impairment associated with Plasmodium falciparum malaria in sub-saharan Africa� Am J Trop Med Hyg� 2004;71(2 Suppl):64-70�

8� Taylor Wr, White NJ� Antimalarial drug toxicity: a review� drug Saf� 2004;27(1):25-61�

9� Omari Aika AA, gamble Carrol L, garner p� Artemether-lumefantrine (six-dose regimen) for treating uncompli-cated falciparum malaria� Cochrane database of Systematic reviews [serial on internet]� 2005; (4): Available from: http://onlinelibrary�wiley�com/doi/10�1002/14651858�Cd005564/abstract�

10� genovese rF, Newman dB� Understanding artemisinin-induced brainstem neurotoxicity� Arch Toxicol� 2008;82(6):379-85�

11� Erickson ri, defensor EB, Fairchild dg, Mirsalis JC, Steinmetz KL� Neurological assessments after treatment with the antimalarial beta-arteether in neonatal and adult rats� Neurotoxicology� 2011;32(4):432-40�

12� Tucci d, Merson MH, Wilson BS� A summary of the literature on global hearing impairment: current status and priorities for action� Otol Neurotol� 2010;31(1):31-41�

13� idro r, Marsh K, John CC, Newton CrJ� Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome� pediatr res� 2010;68(4):267-274�

14� ramkalawan TW, davis AC� The effects of hearing loss and age of intervention on some language metrics in young hearing-impaired children� British Journal of Audiology� 1992;26(2):97-107�

15� Al Serouri AW, grantham-Mcgregor SM, greenwood B, Costello A� impact of asymptomatic malaria parasi-taemia on cognitive function and school achievement of schoolchildren in the yemen republic� parasitology� 2000;121 ( pt 4):337-45�

Corresponding Authordr Eric Fong School of public Health and Tropical Medicine, James Cook University, Townsville

Email: eric�fong@my�jcu�edu�au

16� Nankabirwa J, Wandera B, Kiwanuka N, Staedke Sg, Kamya Mr, Brooker SJ� Asymptomatic plasmodium infection and cognition among primary schoolchildren in a high malaria transmission setting in Uganda� Am J Trop Med Hyg� 2013 Apr 15�

17� Thuilliez J, Sissoko MS, Toure OB, Kamate p, Berthelemy JC, doumbo OK� Malaria and primary education in Mali: a longitudinal study in the village of doneguebougou� Soc Sci Med� 2010;71(2):324-34�

18� Fernando d, de Silva d, Carter r, Mendis KN, Wickremasinghe r� A randomized, double-blind, placebo-con-trolled, clinical trial of the impact of malaria prevention on the educational attainment of school children� Am J Trop Med Hyg� 2006 Mar;74(3):386-93�

19. Kotby MN, Tawfik S, Aziz A, Taha H. Public health impact of hearing impairment and disability. Folia Phoniatr Logop� 2008;60(2):58-63�

20� Zhao SZ, Mackenzie iJ� deafness: malaria as a forgotten cause� Ann Trop paediatr� 2011;31(1):1-10�

21� Adjei gO, goka BQ, Kitcher E, rodrigues Op, Badoe E, Kurtzhals JA� reversible audiometric threshold changes in children with uncomplicated malaria� J Trop Med� 2013;2013:360540�

22� Schmutzhard J, Kositz CH, Lackner p, dietmann A, Fischer M, glueckert r, et al� Murine malaria is associated with significant hearing impairment. Malar J. 2010;9:159.

23� dunmade Ad, Segun-Busari S, Olajide Tg, Ologe FE� profound bilateral sensorineural hearing loss in Nigerian children: any shift in etiology? J deaf Stud deaf Educ� 2007 Winter;12(1):112-8�

24� Adjei g, Kurtzhals J, rodrigues O, Alifrangis M, Hoegberg L, Kitcher E, et al� Amodiaquine-artesunate vs artemether-lumefantrine for uncomplicated malaria in Ghanaian children: a randomized efficacy and safety trial with one year follow-up� Malaria Journal� 2008;7(1):127�

25� Hutagalung r, Htoo H, Nwee p, Arunkamomkiri J, Zwang J, Carrara Vi, et al� A case-control auditory evaluation of patients treated with artemether-lumefantrine� Am J Trop Med Hyg� 2006 Feb;74(2):211-4�

26� Carrasquilla g, Barón C, Monsell EM, Cousin M, Walter V, Lefèvre g, et al� randomized, prospective, three-arm study to confirm the auditory safety and efficacy of artemether-lumefantrine in Colombian patients with uncomplicated Plasmodium falciparum malaria� The American Journal of Tropical Medicine and Hygiene� 2012 January 1, 2012;86(1):75-83�

27� Toovey S, Jamieson A� Audiometric changes associated with the treatment of uncomplicated falciparum ma-laria with co-artemether� Trans r Soc Trop Med Hyg� 2004 May;98(5):261-7; discussion 268-9�

28� gurkov r, Eshetu T, Miranda i, Berens-riha N, Mamo y, girma T, et al� Ototoxicity of artemether/lumefantrine in the treatment of falciparum malaria: a randomized trial� Malaria Journal� 2008;7(1):179�

29. Freeland A, Jones J, Mohammed NK. Sensorineural deafness in Tanzanian children--is ototoxicity a significant cause? A pilot study� int J pediatr Otorhinolaryngol� 2010 May;74(5):516-9�

30� Flanagan KL, Buckley-Sharp M, doherty T, Whitty CJ� Quinine levels revisited: the value of routine drug level monitoring for those on parenteral therapy� Acta Trop� 2006 Feb;97(2):233-7�

31� Tange rA, dreschler WA, Claessen FA, perenboom rM� Ototoxic reactions of quinine in healthy persons and patients with Plasmodium falciparum infection� Auris Nasus Larynx� 1997 Apr;24(2):131-6�

32� Schneider C, Adamcova M, Jick SS, Schlagenhauf p, Miller MK, rhein Hg, et al� Antimalarial chemoprophy-laxis and the risk of neuropsychiatric disorders� Travel Med infect dis� 2013 Mar-Apr;11(2):71-80�

33. Toovey S. Mefloquine neurotoxicity: A literature review. Travel Medicine and Infectious Disease. 2009;7(1):2-6�

34. Frey SG, Chelo D, Kinkela MN, Djoukoue F, Tietche F, Hatz C, et al. Artesunate-mefloquine combination therapy in acute Plasmodium falciparum malaria in young children: a field study regarding neurological and neuropsy-chiatric safety� Malar J� 2010;9:291�

35� Carrara V, phyo A, Nwee p, Soe M, Htoo H, Arunkamomkiri J, et al� Auditory assessment of patients with acute uncomplicated Plasmodium falciparum malaria treated with three-day mefloquine-artesunate on the north-western border of Thailand� Malaria Journal� 2008;7(1):233�

36. Wise M, Toovey S. Reversible hearing loss in temporal association with chemoprophylactic mefloquine use. Travel Med infect dis� 2007 Nov;5(6):385-8�

existing knowledge of quinine as an ototoxic drug that is used in malaria treatment� Limited available evidence does not currently support the hy-pothesis that mefloquine is ototoxic. There were no other clinical reports of ototoxicity of other antimalarial drugs, including atovaquone-proguanil, sulfadoxine-pyrimethamine, or halofantrine�

ConclusionsThis review of the literature found a small number of studies that support an association between malaria and hearing loss� This suggests that further re-search should be done to better clarify this association and its impact on the individual� in particular, studies should concentrate on the long-term conse-quences, if any, of this phenomenon� Most antimalarial agents appear not to cause ototoxic reactions, with the exception of quinine, which has a predict-able response. The evidence for deafness due to mefloquine is poor. The lack of strong evidence of a direct correlation between malaria and hearing loss may be because any deafness suffered from malaria is not appreciated or is underreported� This might be compounded by the fact that the issue has not been well recognised, suggested by the limited studies within the literature� in addition, there are few studies which record a baseline auditory threshold before becoming infected with malaria� Both clinical and non-clinical studies support further clinical research to identify an association and clarify mecha-nisms that cause deafness during a malarial episode, as this may provide a strategy to prevent potentially avoidable cases of hearing loss�


CASE REPORT

TB or not TB: The clinical and diagnostic challenge of suspected pericardial tuberculosisVictoria g Hall

Royal Melbourne Hospital, Grattan St, Parkville VIC

ABSTRACT

A 61-year-old Vietnamese-born male presented to an inner-city tertiary hos-pital after urgent medivac retrieval from Vietnam� He had a presumed diagno-sis of severe cardiogenic failure, and on admission rapidly deteriorated with a large pericardial effusion and cardiac tamponade seen on echocardiogram� He was admitted to the intensive care unit, and underwent investigation and treatment for suspected tuberculous (TB) pericarditis� All diagnostic mea-sures available, however, were negative for TB� This case highlights the clini-cal and diagnostic challenge of pericardial TB, and that further research is needed to aid clinicians�

Keywords: tuberculosis, pericarditis, diagnosis, interferon-gamma, pCr


introductionTuberculous pericarditis is an uncommon complication of TB, and rarely seen in the developed world due to low overall prevalence�1 However, world-wide, TB is still a major cause of morbidity and mortality, with progress sub-stantially undermined by the HiV epidemic and emerging drug resistance�2

it remains a disease of poverty, linked to overcrowding and undernutrition�2 The increasing prevalence of co-infection with HiV in developing countries has led to a marked increase in rates of TB pericarditis, and in endemic areas, aetiology of pericarditis is most commonly attributed to TB�1

Case reportA 61-year-old Vietnamese-born male, having lived in Australia for the past six years, presented to a large inner-city tertiary hospital after urgent medivac retrieval from Vietnam. He had a background history notable for atrial fibrilla-tion (on warfarin), with pacemaker for tachy-brady syndrome, hypertension, dyslipidemia and non-alcoholic steatohepatitis� He was previously independ-ent, a practising Buddhist, and lived alone with a supportive family close by� He often holidayed in Vietnam to visit friends and family�

Whilst in Vietnam he was admitted to hospital two months prior to his trans-fer with severe biventricular heart failure� His admission was complicated by an extended-spectrum beta-lactamase E. coli catheter-related sepsis, requir-ing transfer to the intensive care unit (iCU)� despite a prolonged course of meropenem and amikacin, he had persistent hypotension and anasarca un-responsive to aggressive diuresis� Echocardiography performed in Vietnam was reported as asymmetric hypertrophic cardiomyopathy with no evidence of flow obstruction and moderate pulmonary hypertension.

On admission to hospital in Australia, the patient appeared to be in cardio-genic shock, with a systolic blood pressure of 85 mmHg� He was jaundiced, with tender hepatomegaly and severe peripheral oedema� Chest x-ray (Fig� 1) showed a large globular heart and bilateral pleural effusions� The patient was afebrile, with normal white cell count and C-reactive protein of 20 mg/L� Liver function tests revealed mixed picture deranged liver enzymes, hyperbiliru-binemia and hypoalbuminemia� The working diagnosis was one of ongoing cardiogenic failure, complicated by altered conscious state and congestive hepatopathy due to severe right heart failure�

Figure 1 initial chest x-ray

A few hours after admission the patient required emergency attention for hypotension, with systolic blood pressure recorded as 75 mmHg� An urgent bedside transthoracic echocardiogram (TTE) demonstrated a large pericar-dial effusion (4 cm), preserved left ventricular function with mild left ventric-ular hypertrophy, and evidence of early signs of cardiac tamponade� There was no evidence of hypertrophic cardiomyopathy� pericardiocentesis was performed, with 1.2 litres of blood-stained pericardial fluid drained. Results of the pericardial fluid analysis, showing an exudate, are detailed in Table 1.

The patient was reviewed by the infectious disease team, who thought that a diagnosis of pericardial TB was unlikely, due to the absence of prodomal symptoms and no known contacts with TB, with the only risk factor being country of birth� They suggested investigation for TB, a liver cirrhosis work-up including abdominal ultrasound, and to continue meropenem to cover for ongoing possible sepsis�

On day three of admission, the patient was again hypotensive and febrile� Vancomycin was added to meropenem to cover for nosocomially-acquired infection� repeat TTE showed small pericardial effusion and normal peri-cardial thickness� The patient was transferred to the iCU for haemodynamic monitoring and support�

All cultures as part of the septic screen were negative, as were sputum samples for acid-fast bacilli and a QuantiFErON-TB gold test� Abdominal ultrasound revealed small volume ascites and the liver cirrhosis screen was normal� Further investigations were done: rheumatological screen, serology for schistosomiasis and stronglyloides, cytomegalovirus, Epstein-Barr virus and HiV serology; all were negative�

A computed tomography of the chest, abdomen and pelvis was ordered for further assessment and to investigate the possibility of malignancy� it re-vealed a re-accumulated large pericardial effusion and large bilateral pleural effusions� There was no evidence of malignancy or lymphadenopathy�

The impression from the infectious disease team was that there was not enough evidence to diagnose and treat pericardial TB� However, as it re-mained the primary differential diagnosis, pericardial and pleural biopsy was recommended� This occurred uneventfully (Table 2) and the patient was commenced on standard anti-TB therapy and high-dose prednisolone on day eight of admission�

The patient remained in the iCU for a further three weeks with minimal clini-cal response. Ongoing issues of hypotension requiring significant inotropic support, severe right heart failure, sepsis unresponsive to broad antimicro-bial treatment, and multi-organ failure ensued� The patient remained on anti-TB therapy and high-dose prednisolone� All results, including the pericardial


biopsy, were negative for TB� repeat CT chest however revealed new right upper lobe pulmonary nodules and sub-centimetre mediastinal lymph nodes not noted on previous imaging�

in light of this, and due to ongoing haemodynamic instability, the patient underwent a full heart study. Haemodynamic findings were consistent with constriction or restriction. Definitive diagnosis could not be made as the patient was in atrial fibrillation and respiratory variation was not able to be assessed due to the patient’s conscious state� A pericardectomy, from these results, was not recommended�

despite maximal iCU support, the patient’s clinical state continued to dete-riorate� A decision was made, in accordance with the family, to cease active management� The patient was palliated and died one day later� Unfortunately, due to religious beliefs, an autopsy was not performed�

discussion TB pericarditis typically presents with non-specific symptoms of fever, night

sweats and weight loss4; cough, dyspnoea and pleuritic chest pain are also common1� A minority of patients, however, present with features of constric-tive pericarditis;5,6 of these, most present with symptoms of cardiac failure�6

pericardial involvement by M. tuberculosis commonly develops through lymphatic spread from adjacent lung, tracheal, bronchial or mediastinal lymph nodes, or via haematogeneous spread from primary infection�1,4 it is often due to reactivation and the primary source of infection is not found� it is the immune response to the viable acid-fast bacilli in the pericardium that is responsible for morbidity, as a hypersensitivity reaction mediated by TH1 lymphocytes causes the resultant pericardial effusion�4

Constrictive pericarditis tends to manifest in one of three syndromes: cardiac tamponade, constrictive pericarditis, or effusive-constrictive pericarditis�6

Effusive-constrictive pericarditis has evidence of both constriction and peri-cardial effusion, complicated by early signs of cardiac tamponade�6 it often becomes apparent after pericardiocentesis because constriction remains even after removal of pericardial fluid. Chronic granulomatous inflammation

Table 1 Results of pericardial fluid analysis

Table 2 results of pericardial biopsy analysis

INVESTIGATION FINDINGS

Sodium

potassium

Chloride

Creatinine

Urea

glucose

Albumin

Lactate dehydrogenase

140 mmol/L

3�6 mmol/L

95 mmol/L

89 umol/L

10�9 mmol/L

4�3 mmol/L

23 g/L

957 iU/L

Microscopy & culture Leukocytes +

No organisms seen on gram stain�

Microscopy for TB Auramine-rhodamine stain: no acid-fast bacilli detected

Cytology The smears contain scant mesothelial cells with foamy macrophages and inflammatory cells including eosinophils. No malignant cells are identified. Consistent with inflammation.

M. tuberculosis complex dNA pCr

Negative

Mycobacterial culture Negative (after four weeks)

INVESTIGATION FINDINGS

HistopathologySections show fibroadipose connective tissue. The stroma contains a sparse lymphoplasmacytic chronic inflammatory cell infiltrate. No active or granulomatous inflammation is seen. No refractile foreign body material is identified. There is no evidence of malignancy. Conclusion: mild non-specific chronic inflammation.

Microscopy for TB Auramine-rhodamine stain: no acid-fast bacilli detected

M. tuberculosis complex dNA pCr

Negative

Mycobacterial culture Negative


References1� Stout J� Tuberculous pericarditis� Uptodate, 2013� Available from: http://www�uptodate�com/contents/tuber-

culous-pericarditis?source=search_result&search=tuberculous+pericarditis&selectedTitle=1~18 (accessed 22 May 2013)

2� World Health Organization� Tuberculosis Fact Sheet� Available from: http://www�who�int/mediacentre/fact-sheets/fs104/en/ (accessed 22 May 2013)

3� Hoa NB, Sy dN, Nhung NV, Tiemersma EW, Borgdorff MW, Cobelens FgJ� National survey of tuberculosis prevalence in Viet Nam� Bulletin of the World Health Organization 2010:88:273-280� Available from: http://www�who�int/bulletin/volumes/88/4/09-067801/en/

4� Bongani M, Burgess LJ, Anton Fd� Tuberculous pericarditis� Circulation 2005; 112:3608-3616�

5� Mayosi BM, Ntsekhe M, Bosch J, pogue J, gumedze F, Badri M et al� rationale and design of the investigation of the Management of pericarditis (iMpi) trial: a 2 × 2 factorial randomized double-blind multicenter trial of adjunctive prednisolone and Mycobacterium w immunotherapy in tuberculous pericarditis� American Heart Journal 2013;165(2):109-115�

6� Hoit Bd� Constrictive pericarditis� Uptodate, 2013� Available from: http://www�uptodate�com/contents/con-strictive-pericarditis?source=search_result&search=tuberculous+pericarditis&selectedTitle=4~18 (accessed 22 May 2013)

7� yen-Wen L, Huey-ru T, Wen-Huang L, Li-Jen L, Jyh-Hong C� Tuberculous constrictive pericarditis with con-current active pulmonary tuberculosis infection: a case report� Cases Journal 2009;2:7010�

8� reuter H, Burgess L, van Vuuren W, doubell A� diagnosing tuberculous pericarditis� European Heart Journal 2006;99(12):827�

9� Biglino A, Crivelli p, Concialdi E, Bolla C, Montrucchio g� Clinical usefulness of ELiSpOT assay on pericardial fluid in a case of suspected tuberculous pericarditis. Infection 2008;36:601-604.

leads to thickened, fibrosed pericardium with evidence of calcification.6,7 This underlying pathology inhibits adequate diastolic filling, reducing venous re-turn and lowering cardiac output�6

prompt diagnosis and treatment of constrictive pericarditis due to TB is paramount to reduce mortality�7,8,9 diagnosis relies on isolation of tubercle bacilli in pericardial fluid, which is often difficult.9 A definitive diagnosis is only made with one of positive culture, acid-fast bacilli stain in pericardial fluid or detection of tubercle bacilli, and/or typical caseating granuloma on pericardial biopsy�2,8 it is considered likely in the presence of pericardial ef-fusion and TB isolated from sputum or other sites, with a positive clinical response to anti-TB therapy�2,9

Negative initial investigations do not rule out TB as the cause of pericardi-tis. Smears with Ziehl-Neelsen (ZN) staining of pericardial fluid have poor sensitivity, with only 40-60% being positive.8 Culture is often slow, taking up to 6-8 weeks, and is also of low sensitivity�2,8 Empiric therapy is often commenced with clinicians relying heavily on clinical grounds only for diag-nosis�8 However, this subjects the patient to unnecessary adverse effects and long duration of anti-TB chemotherapy�8

initial evaluation of TB pericarditis is as demonstrated by the case� Echo-cardiography is useful and accurate for the detection of pericardial effusion and tamponade�2,8 The suggestion of tamponade is an absolute indication for pericardiocentesis. Resultant pericardial fluid analysis due to TB is classically an exudate, with high protein level and lymphocytic counts�2

Unfortunately, due to resource limitation, pericardial fluid in our case was not analysed for adenosine deaminase concentration (AdA)� its measurement has been found to be useful, with levels ranging from 30-60 U/L indicative of the presence of TB pericarditis�2 An observational study by reuter et al8 on 233 patients in South Africa found that an AdA level of >40 U/L had an 87% sensitivity and 89% specificity for TB. Another study in Korea used both AdA and carcinoembryonic antigen to investigate the aetiology of pericardial fluid. They found no significant difference in ADA level between the group of patients with definite TB and those with suspected TB. Their study found a sensitivity and specificity of 93% and 97% respectively for a cut-off level of >40 U/L�10 Higher levels of AdA have also been found to be a prognostic indicator for the development of constrictive pericarditis and subsequent pericardectomy�2,11

The advent of testing for pericardial interferon-gamma, using the T�SpOT TB assay, and its diagnostic potential for TB pericarditis has been described in numerous studies�8,9,12,13 The T�SpOT TB assay is an enzyme-linked immuno-spot (ELiSpOT) assay that measures the gamma interferon response of lym-phocytes to the tuberculosis antigens ESAT-6 and CFp-10�13,14 The result is reported as number of iFN-gamma-producing T cells (spot-forming cells)�14 If the spot counts in the TB antigen wells exceed a specific threshold relative to the control wells, an individual is considered positive for M. tuberculo-sis infection�14 The test should also be performed concurrently on peripheral blood; a significantly positive ratio between pericardial and peripheral blood suggests compartmentalisation and adds further evidence to the presence of tuberculous pericarditis�9,12

The TB�SpOT TB assay differs from the QuantiFErON-TB gold in-Tube (QFT-giT) assay used in Australia, an ELiSA-based test that uses three TB antigens (ESAT-6, CFp-10, TB7�7)�14 Both have FDA approval. QFT-GIT is a quantifica-tion of the iFN-gamma response to TB antigens, and is considered positive for M. tuberculosis infection if the response is above a test cut-off�14 The sen-sitivity of T-SPOT.TB has been reported as 90%, superior to that of QFT-GIT, with a sensitivity of 80%. Both have specificity greater than 95%.14 Neither is accurate in the differentiation between latent and active tuberculosis infec-tion�14 There is no available literature on the use of QFT-giT as a diagnostic aid for pericardial TB�

pericardial tissue can be sent for microscopy and culture, and examined his-tologically for granulomatous inflammation and caseous necrosis.1 Biopsy of the pericardium is usually reserved for when clinical suspicion is still high, duration of illness more than 3 weeks, and the aforementioned investigations have not yielded a positive result�1,4 However, it is usually only performed on

patients from non-endemic areas, as it may add further morbidity without diagnostic value�1,4,12

pCr for M. tuberculosis is available, as was performed in this case� Cegielski et al compared the use of pCr, culture and histopathology for diagnosis of TB on either pericardial fluid or tissue biopsy.15 The sensitivity of pCr was higher with tissue specimens (12 of 15; 80%) than with fluid specimens (2 of 13; 15%; P = 0.002).15 in their study, including both specimen types, TB infection was correctly identified by culture in 30 out of 43 patients (70%) compared with 14 out of 28 patients (50%) by PCR.15 There was one false positive pCr result of a patient with Staphyloccocus aureus pericarditis�15

The standard four drug anti-tuberculous therapy remains the cornerstone of treatment of TB pericarditis, with reduction in mortality from 80-90% to 8-17% in HIV-negative patients, and the development of constrictive pericar-ditis reduced from 88% to 10-20%.1

The exact role of adjuvant corticosteroids remains unclear�1,4,7,16,17 Only small studies have been conducted, with two of them before the HiV era� Limited data suggests that the use of corticosteroids can shorten the time of clinical symptoms and prevent fluid reaccumulation.17 Their use does not appear to affect the likelihood of progression to constriction�1 guidelines from the American Thoracic Society, Centers for disease Control, and infectious dis-eases Society of America issued in 2003 support the use of prednisolone 60 mg/day for 4 weeks with a tapering dose over the next 7 weeks�1 Further research is needed, with much anticipated results from the investigation of the Management of pericarditis (iMpi) trial, a large multicentre randomised controlled trial currently underway�5

pericardectomy is indicated in patients with persistent constrictive peri-carditis� The timing and appropriate candidacy for surgical intervention is controversial� Some recommend a trial of medical therapy, with pericardiec-tomy for patients who do not clinically respond after 4 to 8 weeks�1, 4 Others suggest all patients with constrictive pericarditis should undergo pericardec-tomy once medical therapy has commenced�1

Conclusion There is still much to know about tuberculous pericarditis� There is scope for further research in diagnosis and clinical management, including the use of corticosteroids� TB pericarditis remains an uncommon but important clinical manifestation of extra-pulmonary TB, requiring a high index of suspicion on the clinician’s behalf� Worldwide, ongoing measures to reduce the incidence of infection with M. tuberculosis must be continued with vigilance�


Corresponding Authordr Victoria g Hall royal Melbourne Hospital, grattan St, parkville ViC

Email: victoriahall26@gmail�com

Case reportA 24-year-old Victorian sheep officer presented to her general practitioner in June 2009 with a 3-month history of tiredness, intermittent headaches, dry cough, vomiting and diarrhoea� On presentation, all her vital signs and physical examination were unremarkable, except that she was obese with a body mass index of 35� investigations included full blood examination, elec-trolytes, thyroid function test, iron, vitamin B12, folate and coeliac serology; all were within normal limits� infectious diseases screening for toxoplasmo-sis and Epstein-Barr virus was negative� Cytomegalovirus igg was positive, but igM was negative� Subsequent Q fever serology (panbio ELiSA, Alere) revealed positive phase 2 igg and negative phase 2 igM, whereas the phase 1 complement fixation titre (CFT) was 16 and phase 2 CFT was 8 (Table 1). The pathologist’s interpretation was ‘Q fever serology suggestive of chronic Q fever infection� The seropositivity unlikely to be due to vaccination’�2

The patient returned for follow up a few months later in October 2009� She continued to experience intermittent headaches, fatigue, dry cough and vom-iting� On further questioning, she had received Q fever vaccination on 19th

March 2009, with a negative pre-vaccination test performed on 12th March 2009, one week prior to the immunisation� She was tested by her company as she took part in a Sheep Centres for research Excellence project looking at DNA markers in specific recorded flocks from around the state. Being a sheep officer, her other duties involved attending abattoirs for carcase com-petitions, as well as going to sheep yards, shearing sheds, and sale yards to investigate sheep mortalities� She recalled that she had commenced work three weeks prior to the testing� The patient’s employer did not enquire about her Q fever vaccination status prior to her employment and the employer was not concerned that she started work prior to being tested and immunised� Furthermore, the patient was unaware that she needed to avoid exposure to Q fever for two weeks following the vaccination, as it takes approximately two weeks for protective immunity to develop�3

Further investigations to exclude Q fever complications were normal, includ-ing transthoracic echocardiogram, chest X-ray, and brain computed tomog-raphy scan� repeat full blood examination revealed mild leukocytosis (11�8 x 109/L; reference range (rr) 4-11 x 109/L) and lymphocytosis (4�1 x 109/L; rr 1-4 x 109/L)� Erythrocyte sedimentary rate was raised (23 mm/hr; rr, <12 mm/hr)� Brucellosis and leptospirosis serology was negative� repeat Q fever serology was identical to that performed earlier�

The patient was referred to an infectious disease physician� A 4-week course of doxycycline 100 mg twice daily was prescribed� in the following month, the patient reported moderate improvement in symptoms, with less cough, fewer headaches and resolution of diarrhoea� in december 2009, the patient still complained of ongoing fatigue, dizziness, cough, headache and myalgia� in February 2010, her symptoms remained the same� Q fever serology was again repeated which revealed a reduction in the level of phase 1 CFT (from 16 to 8)� Other serological parameters remained the same (see Table 1)�

CASE REPORT

An unusual case of Q fever in an immunised sheep officerFrank C H Ng1,2 and Peter A leggat2,3

1. Diamond Creek Medical Centre, Diamond Creek, Victoria, Australia

2. School of Public Health, Tropical Medicine and Rehabilitation Sciences, James Cook University, Townsville, Queensland, Australia

3. School of Public Health, University of the Witwatersrand, Johannesburg, South Africa

ABSTRACT

It is often thought that Q fever vaccination is 100% protective against the disease� An unusual case of Q fever and its debilitating consequences is de-scribed here in a sheep industry development officer, who had been immun-ised� This report highlights the need for further research into improving Q fever testing and taking appropriate preventive measures against the disease� An urgent review of the current occupational health and safety policy is rec-ommended, with implementation of universal mandatory Q fever immunisa-tion for all new abattoir, cattle, goat, sheep and other workers, who may be exposed to Q fever, prior to the commencement of any field work.

Keywords: Q fever, zoonosis, vaccination, agriculture, prevention


BackgroundQ fever is a common zoonosis, with an almost worldwide distribution, caused by Coxiella burnetii.1 Farm animals and pets are the principal reservoirs of in-fection and transmission to humans is usually via inhalation of contaminated aerosols� Occupational groups with close association with farm or wild ani-mals are most at risk� immunisation is usually protective� A case of Q fever in a previously immunised Victorian sheep industry development officer (a ‘sheep officer’) is presented. In general, the qualification requirements of a sheep officer include an undergraduate degree in the areas of science or agriculture, with optional industrial training or postgraduate education� At the time of the project, there was universal no Q fever vaccination program nor a requirement for vaccination in place for new staff such as this sheep officer. Although presumably she would have been aware of the disease, there was no formal training in prevention of Q fever required for the role�

10� Koh KK, Kim EJ, Cho CH, Choi MJ, Cho SK, Kim SS et al� Adenosine deaminase and carcinoembryonic antigen in pericardial effusion diagnosis, especially in suspected tuberculous pericarditis� Circulation 2004;89:2728-2735�

11. Komsuoğlu B, GöldelïO, Kulan K, Komsuoğlu SS. The diagnostic and prognostic value of adenosine deaminase in tuberculous pericarditis� European Heart Journal 1995;16(8):1126�

12� Mehta pK, raj A, Singh N, Khuller gK� diagnosis of extrapulmonary tuberculosis by pCr� immunology and Medical Microbiology 2012;66:20-36�

13� Bathoorn E, Limburg A, Bouwman JJ, Bossink AW, Thijsen SF� diagnostic potential of an enzyme-linked im-munospot assay in tuberculous pericarditis� Clinical Vaccine immunology 2011;18:874-878�

14� Madhukar p, Menzies d� interferon-gamma release assays for diagnosis of latent tuberculosis infection� Uptodate, 2013� Available from: http://www�uptodate�com/contents/interferon-gamma-release-assays-for-diagnosis-of-latent-tuberculosis-infection?source=search_result&search=IGRA&selectedTitle=1%7E60 (ac-cessed 22 May 2013)

15� Cegielski Jp, devlin BH, Morris AJ, Kitinya JN, pulipaka Up, Lema LE et al� Comparison of pCr, culture, and histopathology for diagnosis of tuberculous pericarditis� Journal of Clinical Microbiology 1997;35:3254�

16. Maisch B, SeferovićPM, RistićAD, Erbel R, Rienmüller R, Adler Y et al. Guidelines on the diagnosis and man-

agement of pericardial diseases executive summary; the task force on the diagnosis and management of pericardial diseases of the European Society of Cardiology� European Heart Journal 2004;25(7):587�

17� Al-Shehri F, Chan K, dennie C, Veinot J� Tuberculous pericarditis� Current Cardiology reviews 2005;1(2):165-169�

18� Critchley JA, young F, Orton L, garner p� Corticosteroids for prevention of mortality in people with tuberculo-sis: a systematic review and meta-analysis� Lancet infectious diseases 2013;13(3):16-188�


References1� Maurin M, raoult d� Q fever� Clinical Microbiology reviews 1999;12:518-53�

2� The royal College of pathologists of Australia� Q fever antibodies – serum� rCpA Manual� Updated May 28, 2006� [accessed 2014 Feb 7]� Available from: http://www�rcpamanual�edu�au/index�php?option=com_pttests&task=show_test&id=26&itemid=27

3� Worswick d, Marmion Bp� Antibody responses in acute and chronic Q fever and in subjects vaccinated against Q fever� Medical Microbiology 1985;19:281-96�

4. Australian Government Department of Health and Ageing. National Notifiable Diseases Surveillance System. Number of notifications by year, Australia, 2005 to 2009. Available from: http://www.aihw.gov.au/australias-health-2010-data-tables/?id=6442475642 (accessed dec 17 2013)�

5� Fournier pE, Marrie TJ, raoult d� diagnosis of Q fever� Journal of Clinical Microbiology 1998;36: 1823�

6� CSL Biotherapies� Q-VAX®� Approved product information� Updated Nov, 2013� Available from: http://www�csl�com�au/s1/cs/auhq/1196562765747/Web_product_C/1196562634452/productdetail�htm (accessed Feb 7 2014)�

7. Ackland JR, Worswick DA, Marmion BP. Vaccine prophylaxis of Q fever. A follow-up study of the efficacy of Q-Vax (CSL) 1985-1990� Medical Journal of Australia 1994;160:704-8�

8� Q fever [revised 2010 Aug]� in: eTg complete [Cd-rOM]� Melbourne: Therapeutic guidelines Limited, 2012�

9� raoult d, Houpikian p, Tissot dH, et al� Treatment of Q fever endocarditis: comparison of 2 regimens contain-ing doxycycline and ofloxacin or hydroxychloroquine. Archives of Internal Medicine 1999;159:167-73.

10� Terheggen U, Leggat pA� Clinical manifestations of Q fever in adults and children� Travel Medicine and infec-tious disease 2007;5:159-64�

11� Ayres Jg, Smith Eg, Flint N� protracted debility and fatigue after acute Q fever� Lancet 1996; 347:978-9�

12� Wildman MJ, Smith Eg, groves J, et al� Chronic fatigue following infection by Coxiella burnetii (Q fever): ten-year follow-up of the 1989 UK outbreak cohort� Quarterly Journal of Medicine 2002;95:527-538�

13� Marmion Bp, Shannon M, Maddocks i, et al� protracted debility and fatigue after acute Q fever� Lancet 1996;347:977-8�

14� penttila iA, Harris rJ, Storm p, et al� Cytokine dysregulation in the post-Q-fever fatigue syndrome� Quarterly Journal of Medicine 1998;91:549-60�

Corresponding Authordr Frank CH Ng diamond Creek Medical Centre, 82 Main Hurstbridge rd, diamond Creek, ViC, 3089, Australia

Email: fch_ng@hotmail�com

The patient continued to experience fatigue with minimal exertion physically and mentally� Work performance had been greatly affected and she could only work up to 5 hours/day� Her headaches and dizziness persisted over the next 12 months� Worker’s compensation was involved and the claim was accepted and substantiated� On occasions when she wanted to work longer hours such as going to field trips, she often had to spend the next day in bed, recovering from her exertion� in december 2010, she was diagnosed with post-Q fever fatigue syndrome by an infectious diseases expert� No further courses of antibiotics were prescribed� She was referred to a psychologist for ongoing support and counselling� due to fatigue and impaired working performance, she constantly experienced frustration and low mood� in Au-gust 2011, she was diagnosed with depression and the antidepressant ser-traline was trialled without much improvement� She was unable to work and had to resign from her job in June 2012� Her current treatment comprises regular vitamin d, vitamin C, zinc, and vitamin B12 supplements� To date, the patient has remained debilitated from fatigue and not capable of resuming any work. This has affected her family relationships significantly.

discussionQ fever is a zoonosis caused by the highly infectious C. burnetii, an obligate gram-negative intracellular organism� Cattle, sheep and goats are the main reservoirs for infection in humans� Humans are infected by contact with in-fected animals or their products� in Australia, since the introduction of the Q fever vaccination (first in the abattoirs in 1991, and later more widely in the rural community in 2001-2006 through the National Q Fever Management program), the incidence rate has dropped substantially, from 800 cases an-nually prior to the program to 303 notified cases in 2009.4

in this case, chronic Q fever infection was diagnosed on the basis of both positive phase 1 and phase 2 CFT (titres of 16, 8 respectively)�2 C. burnetii has phase 1 and phase 2 lipopolysaccharides against which the human body mounts an antibody immune response� detecting these antibodies forms the basis of laboratory diagnosis� phase 2 antibodies are positive in acute Q fe-ver, whereas phase 1 antibodies remain elevated in chronic disease�5 during acute Q fever, igM antibodies develop against phase 1 and phase 2 forms, whereas igg antibodies develop only against the phase 2 forms� The current Q fever vaccine (Q-VAX, CSL, Australia)6 composed of a killed suspension of virulent phase 1 organisms, stimulates immune response predominantly against phase 1 antigen�

in Australia, Q-VAX can only be given to people who are tested negative on both serology and skin tests,6 and this patient was no exception� However, she developed dry cough, headaches and diarrhoea shortly after vaccination� There are a few possible scenarios� Firstly, she could have contracted Q fever just prior to the pre-vaccination tests� As the antibodies often only develop 2 to 3 weeks after inoculation,3 it was possible that her pre-vaccination tests were performed prior to the development of detectable antibodies� Secondly, she could have contracted Q fever after being immunised but before the de-velopment of protective immunity, as vaccination during the incubation of Q fever does not prevent the onset of the disease�6 Thirdly, the vaccination might have failed to confer immunity. This would challenge the 100% protec-tion claimed for Q fever vaccination�7

With respect to treatment, doxycycline 100 mg twice daily was recommend-ed to treat acute Q fever�8 Although a prolonged course of treatment is sug-gested to treat chronic Q fever endocarditis,9 there is no universal consensus as to the best treatment for chronic infection� in this instance, as the initial serology was low positive and without any systemic complications, only a one month course of doxycycline was prescribed, with good response�

despite treatment, the patient continued to have symptoms ascribed to post-Q fever fatigue syndrome� patients often present with prolonged lassitude, myalgia, arthralgia, sweats and painful lymphadenopathy�1,10 The dominant symptom is an incapacitating fatigue out of proportion to the degree of prior activity, as exemplified in this case. This often lasts beyond a year, up to more than 10 years�11 A United Kingdom study reported that chronic fatigue was experienced in 65% of Q fever sufferers.12 in Australia, post-Q fever fa-tigue syndrome is the most common chronic sequel to acute Q fever, affect-ing 10-15% of patients.13 it is believed that cytokines and other immune me-diators generated by the dysregulated cell-mediated immunity in response to a persisting low level of C. burnetii antigens, result in the symptoms�14

This case highlights several important issues in relation to microbiology and occupational health� Firstly, more research is needed to ascertain the current vaccine’s claimed protectiveness� Secondly, as the current serology and skin test may not detect recent subclinical infection, there is a need to develop and employ more sensitive diagnostic tests to detect Q fever infection earlier� The use of pCr for earlier diagnosis might be a cost-effective consideration� Most importantly, with respect to occupational safety, there should be an urgent call to review the current occupational safety policy, with implementa-tion of universal mandatory Q fever immunisation of all new abattoir, cattle, goat and sheep workers, that may be exposed to Q fever, prior to the com-mencement of any field work. They should be advised that it takes around two weeks before the vaccination becomes protective and that they should avoid exposure in the meantime�

Acknowledgements We would like to acknowledge A/prof ross philpot, infectious disease physi-cian, for his assistance in the preparation of the manuscript�

Table 1 Q fever CFT serology titres

INVESTIGATION JUNE 2009

OCTOBER 2009

FEBRUARy 2010**

phase 1 CFT titre

16 16 8

phase 2 CFT titre

8* 8 8

phase 2 igM Negative Negative Negative

phase 2 igg positive positive positive

*A single CFT titre of >8 for antibodies to phase II antigen indicates past infection.2

** A trial of doxycycline was given in Nov 2009.



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