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REPUBLIC OF KENYA<br />
MINISTRY OF PUBLIC HEALTH AND SANITATION<br />
<strong>Diagnosis</strong> <strong>and</strong> <strong>Management</strong><br />
<strong>of</strong><br />
Visceral Leishmaniasis (<strong>Kala</strong> <strong>Azar</strong>)<br />
National Guidel<strong>in</strong>es for Health Workers<br />
Revised January 2012
DIAGNOSIS AND MANAGEMENT OF VISCERAL<br />
LEISHMANIASIS (KALA AZAR) IN KENYA
For further <strong>in</strong>formation/enquiries contact:<br />
M<strong>in</strong>istry <strong>of</strong> Public Health <strong>and</strong> Sanitation<br />
Department <strong>of</strong> Disease Prevention <strong>and</strong> Control<br />
Neglected Tropical Disease Program<br />
P.O Box 20750 – 00202 KNH<br />
Nairobi.<br />
Tel: + 254 02 2608366<br />
Fax: + 254 02 2608364<br />
Date pr<strong>in</strong>ted: June 2012<br />
Sponsored by:<br />
Republic <strong>of</strong> Kenya<br />
M<strong>in</strong>istry <strong>of</strong> Public Health <strong>and</strong> Sanitation
Foreword<br />
The review <strong>of</strong> this <strong>Diagnosis</strong> <strong>and</strong> <strong>Management</strong> Guidel<strong>in</strong>e is <strong>in</strong>deed a milestone<br />
<strong>in</strong> the control <strong>of</strong> visceral leishmaniasis <strong>in</strong> the country. This is <strong>in</strong> l<strong>in</strong>e with the<br />
recommendation <strong>of</strong> the WHO Consultative Meet<strong>in</strong>g on Visceral Leishmaniasis<br />
Control: from recommendations to implementation; held from 10-12 November<br />
2010 <strong>in</strong> Geneva.<br />
The diagnosis <strong>and</strong> treatment <strong>of</strong> Visceral Leishmaniasis has been faced with<br />
some challenges. For a long time case diagnosis has relied on splenic/bone<br />
marrow aspirates which can only be carried out by skilled health workers. The<br />
development <strong>of</strong> a rapid diagnostic test kits that can be used by health workers<br />
with only little tra<strong>in</strong><strong>in</strong>g will help <strong>in</strong> case diagnosis even at the lowest health<br />
facilities level.<br />
<strong>Kala</strong> azar treatment has been by use <strong>of</strong> pentavalent animonials, ma<strong>in</strong>ly Sodium<br />
stibogluconate (SSG or Pentostam) <strong>and</strong> Sodium antimoniate (Glucantime).<br />
These drugs can only be adm<strong>in</strong>istered through <strong>in</strong>jection. The drugs are toxic,<br />
with many side effects <strong>and</strong> the treatment is given over a period <strong>of</strong> 30 days. To<br />
overcome some <strong>of</strong> these challenges, WHO through its agents has developed <strong>and</strong><br />
recommended the use <strong>of</strong> new rapid diagnostic test kits that will be easy to use<br />
<strong>and</strong> comb<strong>in</strong>ation therapy that will use lower doses, shorter treatment <strong>and</strong><br />
hospitalization (17 days).<br />
The M<strong>in</strong>istry <strong>of</strong> Public Health <strong>and</strong> Sanitation will endeavour to improve the<br />
conditions <strong>of</strong> patients suffer<strong>in</strong>g from <strong>Kala</strong> azar through adoption <strong>of</strong> new<br />
diagnostic techniques <strong>and</strong> improved treatment regimens. The M<strong>in</strong>istry will<br />
further cont<strong>in</strong>ue to put <strong>in</strong> place as well as promote other measures that can be<br />
used to control <strong>Kala</strong> azar <strong>in</strong> the communities affected.<br />
To achieve this, the M<strong>in</strong>istry <strong>of</strong> Public Health <strong>and</strong> Sanitation has developed a<br />
Multi-year Strategic plan (2011-2015) for the control <strong>of</strong> Neglected Tropical<br />
Diseases <strong>of</strong> which <strong>Kala</strong> azar is one <strong>of</strong> them.<br />
It is expected that the revised <strong>Diagnosis</strong>, Treatment <strong>and</strong> <strong>Management</strong><br />
Guidel<strong>in</strong>es for Visceral Leishmaniasis will play an important role <strong>in</strong> guid<strong>in</strong>g<br />
health workers <strong>and</strong> other health development partners <strong>in</strong> diagnosis, treatment<br />
<strong>and</strong> management <strong>of</strong> the disease <strong>in</strong> endemic districts.<br />
Signed<br />
Dr. S.K. Sharif, MBS, M.Med, MSc<br />
Director <strong>of</strong> Public Health <strong>and</strong> Sanitation
Preface<br />
Treatment <strong>of</strong> visceral leishmaniasis patients <strong>in</strong> Kenya has been by use <strong>of</strong><br />
pentavalent antimonials drugs, ma<strong>in</strong>ly Sodium stibogluconate (SSG or<br />
Pentostam) <strong>and</strong> Glucantime (Sodium antimoniate). These drugs are<br />
adm<strong>in</strong>istered <strong>in</strong>tramuscular/<strong>in</strong>travenously at a dose <strong>of</strong> 20mg/Kg/day for 30 days.<br />
Use <strong>of</strong> antimonials is associated with <strong>in</strong>tense local pa<strong>in</strong> <strong>and</strong> systemic adverse<br />
effects. To overcome some problems associated with these drugs <strong>and</strong> to prevent<br />
the emergence <strong>of</strong> drug resistance, drugs comb<strong>in</strong>ation therapies have been<br />
developed <strong>and</strong> approved for use by WHO.<br />
One <strong>of</strong> the comb<strong>in</strong>ation therapies that have proved successful is SSG <strong>and</strong><br />
Paromomyc<strong>in</strong> (PM). Cl<strong>in</strong>ical trials carried out <strong>in</strong> Kenya at the Kenya Medical<br />
Research Institute (KEMRI) <strong>and</strong> <strong>in</strong> others countries funded by Drugs for<br />
Neglected Diseases <strong>in</strong>itiative (DNDi) have shown that compared to SSG alone,<br />
the SSG + Paromomyc<strong>in</strong> comb<strong>in</strong>ation was associated with reduced mortality<br />
<strong>and</strong> fewer complications dur<strong>in</strong>g treatment. The duration <strong>of</strong> treatment was also<br />
reduced from 30 days to 17 days for SSG <strong>and</strong> PM comb<strong>in</strong>ation regimen.<br />
The review <strong>of</strong> the old Treatment Guidel<strong>in</strong>es has been necessitated by the<br />
development <strong>of</strong> the new comb<strong>in</strong>ation therapy <strong>and</strong> the need to improve <strong>and</strong><br />
st<strong>and</strong>ardize diagnosis <strong>and</strong> treatment procedure <strong>in</strong> the country. The document<br />
provides guidel<strong>in</strong>es for improv<strong>in</strong>g practices by cl<strong>in</strong>ician, nurses <strong>and</strong> laboratory<br />
workers <strong>in</strong> leishmaniasis diagnosis, treatment <strong>and</strong> management.<br />
The VL <strong>Diagnosis</strong> <strong>and</strong> Treatment Guidel<strong>in</strong>es provide <strong>in</strong>formation on new rapid<br />
diagnostics tests as well as the st<strong>and</strong>ard technique <strong>of</strong> microscopic exam<strong>in</strong>ation;<br />
it has also <strong>in</strong>cluded the use <strong>of</strong> comb<strong>in</strong>ation therapy (SSG + Paromomyc<strong>in</strong>) as a<br />
first l<strong>in</strong>e drug. The second l<strong>in</strong>e drugs that may be used for patients with special<br />
need have also been <strong>in</strong>corporated. The document has <strong>in</strong>cluded annexes for<br />
St<strong>and</strong>ard Operat<strong>in</strong>g Procedures (SOPs).<br />
This guidel<strong>in</strong>e has been developed as a h<strong>and</strong> on tool for health workers serv<strong>in</strong>g<br />
<strong>in</strong> endemic districts. It is expected to bridge the gap <strong>in</strong> the knowledge <strong>of</strong> this<br />
disease.<br />
The M<strong>in</strong>istry <strong>of</strong> Public Health <strong>and</strong> Sanitation through the Neglected Tropical<br />
Disease program together with partners will use the document to enhance<br />
diagnosis, treatment <strong>and</strong> management <strong>of</strong> leishmaniasis (<strong>Kala</strong> azar) <strong>in</strong> the<br />
country.<br />
Signed<br />
Dr. Willis Akhwale<br />
Head, Department <strong>of</strong> Disease prevention & control
Acknowledgement<br />
The M<strong>in</strong>istry <strong>of</strong> Public Health <strong>and</strong> Sanitation would like to thank the Director,<br />
M<strong>in</strong>istry <strong>of</strong> Public Health <strong>and</strong> Sanitation Dr. S. K. Sharif <strong>and</strong> the Head,<br />
Department <strong>of</strong> Disease Prevention <strong>and</strong> Control Dr. W. Akhwale for provid<strong>in</strong>g<br />
policy guidance <strong>and</strong> technical direction. Special thanks go to the Dr. Joyce<br />
Onsongo, Disease Prevention <strong>and</strong> Control <strong>of</strong>ficer, World Health Organization<br />
(WHO) for her technical advice.<br />
The M<strong>in</strong>istry would also like to thank Kenya Medical Research Institute, Drugs<br />
for Neglected Diseases <strong>in</strong>itiative (DNDi), <strong>and</strong> Medec<strong>in</strong>s Sans Frontieres - OCG<br />
for their technical support <strong>and</strong> guidance dur<strong>in</strong>g the review <strong>of</strong> the guidel<strong>in</strong>e. The<br />
M<strong>in</strong>istry further acknowledges special support from MSF-OCG <strong>and</strong> Drugs for<br />
Neglected Diseases <strong>in</strong>itiative (DNDi) for fund<strong>in</strong>g the review process.<br />
The M<strong>in</strong>istry is <strong>in</strong>deed thankful to the review team for their <strong>in</strong>valuable time<br />
they put <strong>in</strong> review<strong>in</strong>g this guidel<strong>in</strong>e.<br />
List <strong>of</strong> Review Team<br />
1. Dr. S. K. Sharif Director <strong>of</strong> Public Health <strong>and</strong> Sanitation<br />
2. Dr. Willis Akhwale Head, Department <strong>of</strong> Disease prevention &<br />
Control<br />
3. Dr. Joyce K. Onsongo WHO – Disease Prevention <strong>and</strong> Control<br />
4. Dr. Davis Wachira MOPHS – NTD Programme<br />
5. Mr. Wilson Njeru MOPHS – NTD Programme<br />
6. Ms. Dorothy N. Mwanjuzi MOPHS – NTD Programme<br />
7. Dr. Monique Wasunna KEMRI/DNDi<br />
8. Dr. Robert Kimutai KEMRI/DNDi<br />
9. Dr. Rashid Juma KEMRI<br />
10. Dr. Jane Mbui KEMRI<br />
11. Dr. Margaret Mbuchi KEMRI<br />
12. Dr. Njenga Njoroge KEMRI<br />
13. Mr. Charles Magiri KEMRI<br />
14. Mr. Simon Bolo DNDi<br />
15. Ms Joy Malongo DNDi<br />
16. Dr. Francois Chappuis MSF-OCG/University Hospital Geneva<br />
17. Dr. Elena Velilla MSF- OCG/Kenya<br />
18. Pr<strong>of</strong>. Kirana M. Bhatt University <strong>of</strong> Nairobi
Table <strong>of</strong> Content Page<br />
Foreword ------------------------------------------------------------------------------------------ iii<br />
Preface--------------------------------------------------------------------------------------------- iv<br />
Acknowledgement ------------------------------------------------------------------------------ v<br />
Table <strong>of</strong> content ---------------------------------------------------------------------------------- viii<br />
List <strong>of</strong> Abbreviations & Acronyms ----------------------------------------------------------- ix<br />
Chapter 1----------------------------------------------------------------------------------------- 1<br />
1.0 Introduction ------------------------------------------------------------------------------- 1<br />
1.1 Life Cycle <strong>and</strong> Transmission ---------------------------------------------------------- 2<br />
1.2 Epidemiology ---------------------------------------------------------------------------- 3<br />
1.3 Surveillance case def<strong>in</strong>ition ------------------------------------------------------------ 3<br />
1.4.0 Prevention <strong>and</strong> control ------------------------------------------------------------------ 4<br />
1.4.1 Vector control ---------------------------------------------------------------------------- 4<br />
1.4.2 Personal protection ---------------------------------------------------------------------- 5<br />
1.5 Animal reservoirs ------------------------------------------------------------------------ 5<br />
1.6 Post <strong>Kala</strong> azar Dermal Leishmanisis ------------------------------------------------- 5<br />
1.7 Public awareness ------------------------------------------------------------------------- 5<br />
1.8 Surveillance <strong>and</strong> outbreak response -------------------------------------------------- 5<br />
Chapter 2----------------------------------------------------------------------------------------- 6<br />
2.0 Cl<strong>in</strong>ical presentation <strong>and</strong> diagnosis <strong>of</strong> visceral leishmaniasis -------------------- 6<br />
2.1.1 Cl<strong>in</strong>ical case def<strong>in</strong>ition ----------------------------------------------------------------- 6<br />
2.1.2 Differential diagnosis ------------------------------------------------------------------- 7<br />
2.2.0 Laboratory diagnosis for visceral leishmaniasis ------------------------------------ 8<br />
2.2.1 Parasitological diagnosis --------------------------------------------------------------- 8<br />
2.2.2.0 Serological diagnosis ----------------------------------------------------------------- 8<br />
2.2.2.1 Direct agglut<strong>in</strong>ation test (DAT) ------------------------------------------------------ 8<br />
2.2.2.2 Rapid diagnostic test ------------------------------------------------------------------- 9<br />
2.2.3.0 Antigen detection test ------------------------------------------------------------------ 10<br />
2.2.3.1 Latex agglut<strong>in</strong>ation test---------------------------------------------------------------- 10<br />
Chapter 3----------------------------------------------------------------------------------------- 11<br />
3.0 <strong>Management</strong> <strong>of</strong> visceral leishmaniasis ----------------------------------------------- 11<br />
3.1 Pr<strong>in</strong>ciples <strong>and</strong> objectives <strong>of</strong> management ------------------------------------------- 11<br />
3.2 Supportive management- --------------------------------------------------------------- 11<br />
3.3.0 Drug treatment --------------------------------------------------------------------------- 12<br />
3.3.1.0 First l<strong>in</strong>e treatment- -------------------------------------------------------------------- 12<br />
3.3.1.1 S<strong>in</strong>gle drug therapy -------------------------------------------------------------------- 12<br />
3.3.1.2 Comb<strong>in</strong>ation therapy------------------------------------------------------------------- 13<br />
3.3.2.0 Second l<strong>in</strong>e treatment ------------------------------------------------------------------ 14<br />
3.3.2.1 Amphoteric<strong>in</strong> B ------------------------------------------------------------------------- 14<br />
3.3.2.2 Liposomal Amphoteric<strong>in</strong> B ----------------------------------------------------------- 14
3.3.3 Def<strong>in</strong>ition <strong>of</strong> treatment outcome <strong>in</strong> visceral leishmaniasis ---------------------- 15<br />
3.3.4 Drugs used <strong>in</strong> the treatment <strong>of</strong> relapse <strong>and</strong> non-responsiveness <strong>of</strong> VL -------- 16<br />
3.3.5 Drugs under cl<strong>in</strong>ical evaluation ---------------------------------------------------- 17<br />
3.3.6 Anti-Leishmanial drugs used <strong>in</strong> other countries ----------------------------------- 17<br />
3.4 Visceral leishmaniasis <strong>and</strong> HIV co-<strong>in</strong>fection --------------------------------------- 18<br />
3.5.0 Post kala azar Dermal Leishmaniasis ---------------------------------------------- 19<br />
3.5.1 Prevalence -------------------------------------------------------------------------------- 19<br />
3.5.2 Presentation ------------------------------------------------------------------------------- 19<br />
3.5.3 <strong>Diagnosis</strong> ---------------------------------------------------------------------------------- 19<br />
3.5.4 Treatment --------------------------------------------------------------------------------- 19<br />
References --------------------------------------------------------------------------------------- 20<br />
Annexes<br />
Annex 1: Guidel<strong>in</strong>e for Splenic Aspiration ------------------------------------------------- 23<br />
Annex 2: Guidel<strong>in</strong>e on Bone Marrow Aspiration ------------------------------------------ 25<br />
Annex 3: Preparation <strong>and</strong> Sta<strong>in</strong><strong>in</strong>g <strong>of</strong> Aspirates -------------------------------------------- 26<br />
Annex 4: Grad<strong>in</strong>g <strong>of</strong> Splenic Aspirate Smears for Leishmania Amatigotes ----------- 27<br />
Annex 5: Direct Agglut<strong>in</strong>ation Test (DAT) ------------------------------------------------- 29<br />
Annex 6a: A diagram illustrat<strong>in</strong>g the steps for perform<strong>in</strong>g the rk39 rapid<br />
diagnostic test ------------------------------------------------------------------------------------ 33<br />
Annex 6b: Interpretation <strong>of</strong> rK39 rapid diagnostic test results --------------------------- 34<br />
Annex 7: Visceral leishmaniasis diagnostic algorithm ------------------------------------ 36<br />
Annex 8: A summary <strong>of</strong> treatment regimens for visceral leishmaniasis ---------------- 37<br />
Annex 9: Paromomyc<strong>in</strong> Drug Insert --------------------------------------------------------- 38<br />
Figures<br />
Figure 1: Life cycle <strong>of</strong> Leishmaniasis -------------------------------------------------------- 2<br />
Figure 2: A map <strong>of</strong> Kenya show<strong>in</strong>g endemic districts ------------------------------------- 4
List <strong>of</strong> Abbreviations<br />
AIDS Acquired Immuno Deficiency Syndrome<br />
ART Anti Retroviral Therapy<br />
CD4 “T” Helper Lymphocytes<br />
DNDi Drugs for Neglected Diseases <strong>in</strong>itiative<br />
DVB & NTD Division <strong>of</strong> Vector Borne <strong>and</strong> Neglected Tropical<br />
Diseases<br />
DAT Direct Agglut<strong>in</strong>ation Test<br />
ETWG Epidemic Technical Work<strong>in</strong>g Group<br />
HIV Human Immuno-deficiency Virus<br />
IDSR Integrated Disease Surveillance <strong>and</strong> Response<br />
ITMs Insecticide Treated Materials<br />
LLINs Long last<strong>in</strong>g Insecticide Treated Nets<br />
KEMRI Kenya Medical Research Institute<br />
mg Milligram<br />
MOPHS M<strong>in</strong>istry <strong>of</strong> Public Health <strong>and</strong> Sanitation<br />
MSF OCG Medec<strong>in</strong>s Sans Frontieres - Operational Centre<br />
Geneva<br />
NFD Northern Frontier District<br />
NNN Novy McNeal Nicole medium<br />
NPHLS National Public Health Laboratory Services<br />
PKDL Post <strong>Kala</strong> <strong>Azar</strong> Dermal Leishmaniasis<br />
RDTs Rapid Diagnostic Tests<br />
RPMI Roswell Park Memorial Institute medium<br />
SSG Sodium Stibogluconate<br />
TB Tuberculosis<br />
TLC Total Lymphocytes Count<br />
TOC Test <strong>of</strong> Cure<br />
TSS Tropical Splenomegaly Syndrome<br />
VL Visceral Leishmaniasis<br />
WHO DPC World Health Organisation Disease Prevention <strong>and</strong><br />
Control<br />
ZIPP Z<strong>in</strong>c Iod<strong>of</strong>orm Paraff<strong>in</strong> Paste
CHAPTER 1<br />
1.0 Introduction<br />
Leishmaniasis still rema<strong>in</strong>s a public health problem <strong>in</strong> about 22 districts <strong>in</strong><br />
Kenya. The disease is caused by protozoan parasite <strong>of</strong> the Genus Leishmania<br />
<strong>and</strong> transmitted by s<strong>and</strong>flies <strong>of</strong> the genus Phlebotomus. Globally it occurs <strong>in</strong> 88<br />
countries with 500,000 cases <strong>of</strong> Visceral Leishmaniasis (VL) reported annually<br />
<strong>and</strong> 350 million are at risk <strong>of</strong> acquir<strong>in</strong>g the disease. Five countries, namely<br />
India, Sudan, Nepal, Bangladesh <strong>and</strong> Brazil account for 90% <strong>of</strong> the global VL<br />
cases. The disease affects the socially marg<strong>in</strong>alized <strong>and</strong> the poorest<br />
communities who earn less that USD 2 a day. The severe form <strong>of</strong> the disease if<br />
untreated is fatal.<br />
In Kenya, leishmaniasis occurs <strong>in</strong> two forms namely visceral leishmaniasis<br />
(<strong>Kala</strong> azar) <strong>and</strong> cutaneous leishmaniasis (Oriental sore). Even though the<br />
disease is curable, it still causes high morbidity <strong>and</strong> sometimes death due to its<br />
low <strong>in</strong>dex <strong>of</strong> suspicion by health providers, late diagnosis <strong>and</strong> case<br />
management. Treatments are limited to Prov<strong>in</strong>cial <strong>and</strong> district hospitals due to<br />
the fact that available treatments are <strong>in</strong>jectables <strong>and</strong> have toxic side effects.<br />
Moreover, current treatment for Leishmaniasis is not readily available <strong>in</strong> most<br />
health facilities as the drugs are expensive. There is <strong>in</strong>adequate <strong>in</strong>formation on<br />
the prevalence, burden <strong>and</strong> spatial distribution <strong>of</strong> the disease. The disease is<br />
ma<strong>in</strong>ly distributed <strong>in</strong> the arid <strong>and</strong> semi-arid regions. VL is endemic <strong>in</strong> the Rift<br />
Valley <strong>and</strong> Eastern Prov<strong>in</strong>ces, with small foci <strong>in</strong> North Eastern. In Eastern<br />
Prov<strong>in</strong>ce the disease foci has been documented <strong>in</strong> Kitui, Mw<strong>in</strong>gi, Makueni,<br />
Machakos, Tharaka, Marsabit <strong>and</strong> Isiolo districts (Wijers, 1971 Pel<strong>in</strong>zzi et al.,<br />
2006; Herrero, 2008). In Rift Valley, the disease is more common <strong>and</strong> is found<br />
<strong>in</strong> Bar<strong>in</strong>go, Pokot, Turkana, Samburu, Kajiado <strong>and</strong> Laikipia Districts (Mebrahtu<br />
et al., 1987; Mebratu et al., 1988). The exact status <strong>of</strong> the problem <strong>in</strong> North<br />
Eastern <strong>and</strong> the northern parts <strong>of</strong> the country is not well understood due to<br />
<strong>in</strong>accessibility <strong>and</strong> problems associated with diagnosis. However, the disease<br />
has been sporadically reported from Wajir <strong>and</strong> M<strong>and</strong>era Districts <strong>in</strong> North<br />
Eastern Prov<strong>in</strong>ce. The disease also occurs along the Kenya – Ug<strong>and</strong>a <strong>and</strong><br />
Sudan border, <strong>and</strong> little is known on its distribution, vectors species <strong>and</strong><br />
reservoir hosts due to the expansive area.<br />
1
1.1 Life Cycle <strong>and</strong> Transmission<br />
The life cycle <strong>of</strong> Leishmania starts when a female phlebotom<strong>in</strong>e s<strong>and</strong> fly gets<br />
<strong>in</strong>fected with the amastigote stage <strong>of</strong> the parasite through a blood meal <strong>of</strong> an<br />
<strong>in</strong>fected person (Figure1). The parasite develops from amastigotes to<br />
promastigotes <strong>in</strong> the mid gut. The promastigotes then migrate to the salivary<br />
gl<strong>and</strong>s <strong>of</strong> the s<strong>and</strong> fly. The parasites are then transmitted dur<strong>in</strong>g a subsequent<br />
blood meal by the female s<strong>and</strong> fly when it <strong>in</strong>jects <strong>in</strong>fective promastigotes <strong>in</strong>to<br />
the next human victim. The promastigotes are taken up by macrophages where<br />
they develop <strong>in</strong>to amastigotes <strong>and</strong> cont<strong>in</strong>ue to multiply, ruptur<strong>in</strong>g the<br />
macrophages <strong>and</strong> <strong>in</strong>fect<strong>in</strong>g the reticulo-endothelial system organs e.g. spleen,<br />
liver <strong>and</strong> bone marrow.<br />
Figure.1: Life cycle <strong>of</strong> Leishmaniasis<br />
2
1.2 Epidemiology<br />
Visceral leishmaniasis is endemic <strong>in</strong> semi-arid <strong>and</strong> arid areas <strong>of</strong> Rift Valley,<br />
Eastern <strong>and</strong> North Eastern prov<strong>in</strong>ces <strong>of</strong> Kenya. It is estimated that about 4,000<br />
cases occur annually majority <strong>of</strong> who are children aged 5 years <strong>and</strong> young<br />
adults, while 5 million people are at risk <strong>of</strong> <strong>in</strong>fections. The most important foci<br />
rema<strong>in</strong> Bar<strong>in</strong>go, Pokot, Turkana, Wajir, Isiolo, Samburu, <strong>and</strong> Marakwet<br />
districts (figure 2). The disease foci may change to areas previously not known<br />
to be endemic as a result <strong>of</strong> climate change <strong>and</strong> population movements. There<br />
have been several VL outbreaks <strong>in</strong> Kenya with the most recent confirmed <strong>in</strong><br />
Isiolo <strong>and</strong> Wajir districts <strong>in</strong> 2006 <strong>and</strong> 2008<br />
Infection starts with a bite <strong>of</strong> an <strong>in</strong>fected female s<strong>and</strong>fly that <strong>in</strong>jects parasites<br />
<strong>in</strong>to a susceptible host. Incubation period ranges from 2-6 months. The disease<br />
presents with fever, hepatosplenomegaly, general malaise <strong>and</strong> wast<strong>in</strong>g.<br />
However, <strong>in</strong>cubation period <strong>in</strong> non-immune hosts could be as short as 2 weeks<br />
which could result <strong>in</strong> an epidemic.<br />
Some <strong>of</strong> the exposed persons develop severe disease. Factors that <strong>in</strong>crease the<br />
risk <strong>of</strong> develop<strong>in</strong>g disease <strong>in</strong>clude; young age, malnutrition, immunosuppressive<br />
diseases such as HIV, malignancies <strong>and</strong> organ transplantation. Case fatality rate<br />
<strong>of</strong> VL approximates 100% if disease is left untreated. Death is ma<strong>in</strong>ly due to<br />
secondary bacterial <strong>in</strong>fections.<br />
1.3 Surveillance case def<strong>in</strong>ition<br />
A suspected case <strong>of</strong> VL is any person liv<strong>in</strong>g <strong>in</strong>, or who has travelled to, an<br />
endemic area <strong>and</strong> compla<strong>in</strong>s <strong>of</strong> fever <strong>of</strong> more than 2 weeks accompanied by<br />
abdom<strong>in</strong>al swell<strong>in</strong>g <strong>and</strong> <strong>in</strong> whom malaria has been ruled out or has not shown<br />
cl<strong>in</strong>ical response to effective antimalarials.<br />
3
Figure 2: A map <strong>of</strong> Kenya show<strong>in</strong>g endemic districts<br />
1.4.0 Prevention <strong>and</strong> control<br />
The ma<strong>in</strong> control strategies <strong>in</strong>clude early case detection, treatment <strong>of</strong> VL cases<br />
<strong>and</strong> vector control. The aim <strong>of</strong> vector control is the prevention <strong>and</strong> reduction <strong>of</strong><br />
diseases transmission.<br />
1.4.1 Vector control<br />
(a) Use <strong>of</strong> <strong>in</strong>secticide treated bed nets (ITN’s) is a useful strategy as VL<br />
endemic areas are also endemic for malaria. Therefore consistent use <strong>of</strong><br />
long last<strong>in</strong>g <strong>in</strong>secticide nets (LLIN’s) can control both diseases.<br />
(b) Indoor spray<strong>in</strong>g with residual <strong>in</strong>secticide.<br />
(c) Destruction <strong>and</strong> outdoor spray<strong>in</strong>g <strong>of</strong> vector breed<strong>in</strong>g <strong>and</strong> rest<strong>in</strong>g sites.<br />
(d) Use <strong>of</strong> <strong>in</strong>secticide treated materials (ITM’s) e.g. cloths, curta<strong>in</strong>s.<br />
4
1.4.2 Personal protection<br />
(a) Use <strong>of</strong> topical <strong>in</strong>sect repellants.<br />
(b) Wear<strong>in</strong>g long sleeved shirts/blouses <strong>and</strong> trousers when outdoors notably<br />
<strong>in</strong> the even<strong>in</strong>gs.<br />
Nevertheless, cont<strong>in</strong>uous research is needed to guide the plann<strong>in</strong>g <strong>and</strong><br />
implementation <strong>of</strong> vector control activities, especially those aimed at <strong>in</strong>tegrated<br />
vector management.<br />
1.5 Animal reservoirs<br />
Currently VL <strong>in</strong> Kenya is considered anthroponotic (human-human<br />
transmission) as no animal reservoir has been confirmed.<br />
1.6 Post <strong>Kala</strong> <strong>Azar</strong> Dermal Leishmaniasis (PKDL)<br />
<strong>Diagnosis</strong> <strong>and</strong> treatment <strong>of</strong> patients with PKDL is important. These cases are<br />
thought to be the ma<strong>in</strong> reservoirs <strong>of</strong> <strong>in</strong>fection for non <strong>in</strong>fected humans.<br />
1.7 Public awareness<br />
Communities liv<strong>in</strong>g <strong>in</strong> endemic areas should be mobilized <strong>and</strong> sensitized to<br />
recognize disease signs <strong>and</strong> symptoms as well as prevention <strong>and</strong> control<br />
measures.<br />
1.8 Surveillance <strong>and</strong> outbreak response<br />
Disease outbreaks <strong>of</strong> VL occur <strong>in</strong> non-immune populations <strong>in</strong> endemic areas.<br />
When more than the expected number <strong>of</strong> confirmed cases is reported, an<br />
outbreak should be declared. Appropriate outbreak <strong>in</strong>vestigations <strong>and</strong> timely<br />
<strong>in</strong>terventions should then be <strong>in</strong>stituted. The health worker should <strong>in</strong>form the<br />
District Medical Officer <strong>of</strong> Health who <strong>in</strong> turn reports to the Prov<strong>in</strong>cial <strong>and</strong><br />
National level. Thereafter, an Epidemic Technical Work<strong>in</strong>g Group (ETWG)<br />
should be activated to co-ord<strong>in</strong>ate an outbreak control response.<br />
Ongo<strong>in</strong>g surveillance <strong>in</strong> endemic districts should be <strong>in</strong>stituted us<strong>in</strong>g the monthly<br />
morbidity report<strong>in</strong>g tools to detect any change <strong>in</strong> trends <strong>of</strong> the disease<br />
<strong>in</strong>cidence.<br />
5
CHAPTER 2<br />
2.0 Cl<strong>in</strong>ical Presentation <strong>and</strong> <strong>Diagnosis</strong> <strong>of</strong> Visceral Leishmaniasis<br />
Visceral Leishmaniasis <strong>in</strong> Kenya is ma<strong>in</strong>ly a disease <strong>of</strong> children between the<br />
ages <strong>of</strong> 2-15 years with a peak between 12-15 years. The <strong>in</strong>cubation period for<br />
VL is typically 2-6 months but may be shorter or much longer. The onset may<br />
be gradual or acute.<br />
2.1.1 Cl<strong>in</strong>ical case def<strong>in</strong>ition<br />
VL should be suspected <strong>in</strong> a patient from a VL endemic area who presents with<br />
fever for more than two weeks, splenomegaly <strong>and</strong> weight loss <strong>in</strong> whom malaria<br />
has been ruled out or has not shown cl<strong>in</strong>ical response to effective antimalarials.<br />
A typical patient will present with the follow<strong>in</strong>g signs <strong>and</strong> symptoms:<br />
• fever for two week or more<br />
• splenomegaly<br />
• weight loss<br />
• anaemia<br />
• cough<br />
• epistaxis<br />
• hepatomegaly<br />
• body weakness<br />
In rare circumstances, some patients will present with:<br />
• oedema<br />
• jaundice<br />
• vomit<strong>in</strong>g<br />
• jo<strong>in</strong>t pa<strong>in</strong>s<br />
• abdom<strong>in</strong>al pa<strong>in</strong>s<br />
• lymphadenopathy<br />
• diarrhoea<br />
6
2.1.2 Differential Diagnoses<br />
Several diseases that may mimic VL <strong>in</strong>clude but are not limited to:<br />
• Malaria<br />
• Schistosomiasis<br />
• Brucellosis<br />
• Typhoid fever<br />
• Tuberculosis<br />
• Chronic hepatitis<br />
• Liver Cirrhosis<br />
• Lymphomas <strong>and</strong> Leukaemias<br />
• AIDS<br />
• Malnutrition<br />
• Hyperactive Malarial Splenomegaly (HMS) formerly known as Tropical<br />
Splenomegaly Syndrome (TSS)<br />
2.2.0 Laboratory <strong>Diagnosis</strong> for Visceral Leishmaniasis<br />
2.2.1 Parasitological <strong>Diagnosis</strong><br />
A cl<strong>in</strong>ically suspected case can be confirmed us<strong>in</strong>g spleen or bone marrow<br />
aspirate. Splenic aspirates are more sensitive (96%) than aspirates <strong>of</strong> bone<br />
marrow (70-80%) However, splenic aspirates are limited to the hospital sett<strong>in</strong>gs<br />
or health facilities where there is adequate equipment <strong>and</strong> tra<strong>in</strong>ed staff to<br />
manage complications appropriately.<br />
We detect parasites as either amastigote or promastigote stages dur<strong>in</strong>g positive<br />
diagnosis. To detect the amastigote stages, smear <strong>of</strong> tissue aspirates has to be<br />
sta<strong>in</strong>ed by one <strong>of</strong> the Romanowsky sta<strong>in</strong>s (Giemsa, Wright or Leishman sta<strong>in</strong>s)<br />
<strong>and</strong> exam<strong>in</strong>ed under oil immersion. To detect promastigote stages, aspirates can<br />
be <strong>in</strong>oculated <strong>in</strong> NNN medium, RPMI 1640 <strong>and</strong> Schneiders <strong>in</strong>sect medium <strong>and</strong><br />
<strong>in</strong>cubated at ambient temperature (not more than 26°C) for up to 2 weeks.<br />
Promastigotes can be demonstrated <strong>in</strong> a wet preparation <strong>of</strong> the culture observed<br />
under microscopy. Cultures have the risk <strong>of</strong> be<strong>in</strong>g contam<strong>in</strong>ated by bacteria<br />
<strong>and</strong> fungi.<br />
Demonstration <strong>of</strong> parasites <strong>in</strong> spleen, bone marrow aspirate is pro<strong>of</strong> <strong>of</strong> VL.<br />
Identify<strong>in</strong>g amastigotes under the microscope can be a difficult task, requir<strong>in</strong>g<br />
patience, time <strong>and</strong> focused attention. , Inability to f<strong>in</strong>d the amastigotes <strong>in</strong> an<br />
aspirate cannot be a reason to exclude VL. In isolated circumstances, repeat<br />
aspirates performed one week apart need to be obta<strong>in</strong>ed from patients with a<br />
7
strong suspicion <strong>of</strong> VL. Exam<strong>in</strong>e at least 1000 microscope fields for<br />
amastigotes us<strong>in</strong>g X100 oil immersion lens (Annexes: 1, 2, 3 <strong>and</strong> 4).<br />
2.2.2. Serological <strong>Diagnosis</strong><br />
These are immunological tests that detect antibodies aga<strong>in</strong>st Leishmania. In<br />
Kenya, Direct Agglut<strong>in</strong>ation Test (DAT) <strong>and</strong> rK39 based dipsticks have ma<strong>in</strong>ly<br />
been used to screen for VL <strong>in</strong> the field. However, rk39 diagnostic test can now<br />
be used to start treatment <strong>in</strong> areas where parasitological diagnosis can not be<br />
carried out. In other areas with well equipped laboratories, diagnosis is<br />
confirmed by demonstration <strong>of</strong> amastigotes <strong>in</strong> splenic/bone marrow aspirates<br />
<strong>and</strong> promastigotes <strong>in</strong> culture).<br />
2.2.2.1 Direct Agglut<strong>in</strong>ation Test (Freeze dried DAT)<br />
DAT is a sensitive <strong>and</strong> specific test. It is simple <strong>and</strong> can be easily performed<br />
under field circumstances. The DAT is technically easy to perform but requires<br />
tra<strong>in</strong><strong>in</strong>g <strong>and</strong> st<strong>and</strong>ardization. The test measures the serological response to<br />
surface borne antigens <strong>of</strong> whole Leishmania donovani.<br />
DAT can be performed us<strong>in</strong>g a dried blood spot (on filter paper) or serum. This<br />
makes it an excellent test to use at the health centre level. The DAT employs a<br />
test antigen that is prepared from formal<strong>in</strong>-killed promastigote stages <strong>of</strong> L.<br />
donovani cultures, which have been sta<strong>in</strong>ed blue for visibility. The test is semiquantitative,<br />
<strong>and</strong> gives antibody titres rang<strong>in</strong>g from 1:50 (usually 1:100) up to<br />
1:102400 or even higher. The cut-<strong>of</strong>f po<strong>in</strong>t for positive DAT is 1:12,800 <strong>in</strong><br />
endemic areas. It requires a well-tra<strong>in</strong>ed laboratory technical staff to undertake<br />
the procedure. It is a highly sensitive (>95%) <strong>and</strong> specific (>85%) test when<br />
performed accord<strong>in</strong>g to st<strong>and</strong>ardised procedures.<br />
In sett<strong>in</strong>gs where parasitological confirmation is not feasible, the freeze dried<br />
DAT together with classical cl<strong>in</strong>ical features <strong>of</strong> VL can be used for diagnosis at<br />
a cut-<strong>of</strong>f <strong>of</strong> 1:12,800 (Annex 5).<br />
8
2.2.2.2 Rapid Diagnostic Tests<br />
A rapid test is a simple, po<strong>in</strong>t <strong>of</strong> care test that can be used <strong>in</strong> all levels <strong>of</strong> the<br />
health care services <strong>in</strong>clud<strong>in</strong>g the peripheral services to permit prompt diagnosis<br />
to <strong>in</strong>itiate treatment. It does not require a laboratory <strong>and</strong> highly skilled technical<br />
staff <strong>and</strong> the results can be read easily <strong>and</strong> preferably with<strong>in</strong> 30 m<strong>in</strong>utes. A<br />
rapid test must also be affordable <strong>and</strong> possess high sensitivity, specificity, <strong>and</strong><br />
reliability. Several rapid VL tests for use <strong>in</strong> field sett<strong>in</strong>gs have been developed.<br />
rK39 dipstick<br />
The rK39 dipstick is a simple rapid diagnostic test (RDT), which can be<br />
performed easily by health personnel at the lowest health level with results<br />
available with<strong>in</strong> 10-20 m<strong>in</strong>utes (as per manufacturer’s <strong>in</strong>structions). It is a<br />
qualitative membrane based immunoassay for detection <strong>of</strong> antibodies to<br />
Leishmania caus<strong>in</strong>g VL. Currently two commercial rk39 dipstick tests are<br />
available. The <strong>Kala</strong>zar Detect (Inbios, Seattle, USA) was validated <strong>in</strong> Bar<strong>in</strong>go –<br />
Kenya <strong>and</strong> the Opti-LEISH (DiaMed AG, Switzerl<strong>and</strong>/Bio-Rad, South Africa)<br />
<strong>in</strong> Amudat Ug<strong>and</strong>a. The results have been variable. Recent studies done <strong>in</strong><br />
Kenya by KEMRI, DNDi <strong>and</strong> MSF-OCG as well as WHO/TDR suggest that<br />
DiaMed IT LEISH/Bio-Rad can be used to <strong>in</strong>itiate treatment <strong>in</strong> patients with<br />
cl<strong>in</strong>ical manifestations <strong>of</strong> VL <strong>in</strong> sett<strong>in</strong>gs where splenic/bone marrow aspirates<br />
cannot be done (Annex 6a <strong>and</strong> 6b).<br />
Advantages <strong>and</strong> disadvantages <strong>of</strong> rk39 as a rapid diagnostic test (RDTs)<br />
Advantages<br />
• Dipsticks enable <strong>in</strong>dividual patients to be tested at the bedside<br />
• Tests are <strong>in</strong>dividually packaged <strong>and</strong> easy to store/transport<br />
• Little tra<strong>in</strong><strong>in</strong>g <strong>and</strong> no laboratory equipment is needed<br />
• Results are available <strong>in</strong> 10 - 20 m<strong>in</strong>utes<br />
• Results are clear <strong>and</strong> easy to read<br />
• Enables decentralized screen<strong>in</strong>g <strong>of</strong> VL<br />
• Easy to use <strong>in</strong> field sett<strong>in</strong>g dur<strong>in</strong>g an outbreak<br />
• Kits can be transported <strong>and</strong> stored at ambient temperature (up to 30 0 C)<br />
9
Disadvantages<br />
• Cannot dist<strong>in</strong>guish between active <strong>and</strong> past symptomatic or asymptomatic<br />
<strong>in</strong>fections. Therefore <strong>in</strong>terpretation must always be <strong>in</strong> comb<strong>in</strong>ation with<br />
cl<strong>in</strong>ical case def<strong>in</strong>ition <strong>and</strong> diagnosis <strong>of</strong> relapse must rely on parasitology.<br />
• In patients with advanced HIV <strong>in</strong>fection a negative result cannot preclude<br />
the diagnosis <strong>of</strong> VL<br />
NB: Leishmaniasis diagnostic alogarithm has been illustrated <strong>in</strong> Annex 7<br />
2.2.3.0 Antigen detection tests<br />
2.2.3.1 Latex Agglut<strong>in</strong>ation Test to detect Leishmania Antigen <strong>in</strong> Ur<strong>in</strong>e<br />
Soon after <strong>in</strong>fection, Leishmania parasites secrete/excrete prote<strong>in</strong>ous antigens<br />
that accumulate <strong>in</strong> the body <strong>and</strong> then are secreted as waste products <strong>in</strong> blood<br />
<strong>and</strong> ur<strong>in</strong>e.<br />
Detection <strong>of</strong> these antigens may be used as a confirmatory test s<strong>in</strong>ce the<br />
antigens are very specific to the parasites that produce them.<br />
The KAtex antigen detection method is simple to perform, specific <strong>and</strong> can be<br />
done <strong>in</strong> field conditions. The test <strong>in</strong>volves boil<strong>in</strong>g fresh ur<strong>in</strong>e <strong>and</strong> react<strong>in</strong>g it<br />
with monoclonal antibody coated latex on a clean microscope slide. Direct<br />
agglut<strong>in</strong>ation will be an <strong>in</strong>dication <strong>of</strong> Leishmania donovani <strong>in</strong>fection.<br />
NB. The test should be done <strong>in</strong> a dust free room to avoid false positive<br />
reaction. (The test is still under evaluation)<br />
10
CHAPTER 3<br />
3.0 <strong>Management</strong> <strong>of</strong> Visceral Leishmaniasis<br />
3.1 Pr<strong>in</strong>ciples <strong>and</strong> Objectives <strong>of</strong> <strong>Management</strong><br />
The objectives <strong>of</strong> VL treatment are to:<br />
1. Cl<strong>in</strong>ically cure the patient<br />
2. M<strong>in</strong>imize drug toxicity<br />
3. Support the patient’s nutrition <strong>and</strong> hydration status<br />
4. Prevent <strong>and</strong> treat complications<br />
5. Prevent the development <strong>of</strong> drug resistance<br />
The choice <strong>of</strong> drugs for the treatment <strong>of</strong> VL <strong>in</strong> Kenya should be based on:<br />
• Efficacy <strong>and</strong> safety<br />
• Availability<br />
• Cost<br />
3.2 Supportive management<br />
Patients should receive adequate nutrition <strong>and</strong> vitam<strong>in</strong>s supplements where<br />
<strong>in</strong>dicated.<br />
Treat <strong>in</strong>ter-current <strong>in</strong>fections such as:<br />
• Pneumonia <strong>and</strong> otitis media with appropriate antibiotics.<br />
• Ma<strong>in</strong>ta<strong>in</strong> oral hygiene to prevent mouth <strong>in</strong>fections<br />
(cancrum oris) <strong>and</strong> rapidly treat cancrum oris, should it occur,<br />
with metronidazole <strong>and</strong> penicill<strong>in</strong>.<br />
• Ma<strong>in</strong>ta<strong>in</strong> sk<strong>in</strong> hygiene <strong>and</strong> treat sk<strong>in</strong> <strong>in</strong>fections.<br />
• Treat malaria <strong>and</strong>/or tuberculosis if present.<br />
Occasionally, blood transfusion may be required for severe anaemia or bleed<strong>in</strong>g<br />
due to thrombocytopaenia.<br />
In severe epistaxis pack<strong>in</strong>g <strong>of</strong> the nose with gauze with adrenal<strong>in</strong>e or Z<strong>in</strong>c<br />
Iod<strong>of</strong>orm Paraff<strong>in</strong> Paste (ZIPP) is recommended.<br />
11
3.3. Drug treatment<br />
3.3.1.0 First l<strong>in</strong>e VL treatment<br />
3.3.1.1 S<strong>in</strong>gle drug therapy<br />
Sodium stibogluconate is a pentavalent antimony compound <strong>and</strong> conta<strong>in</strong>s<br />
100mg pentavalent antimony per ml. This is the first l<strong>in</strong>e treatment for VL <strong>in</strong><br />
Kenya. Available formulations <strong>in</strong>clude;<br />
1. Pentostam® (SSG) from Glaxo-Smith-Kl<strong>in</strong>e, UK.<br />
Concentration <strong>of</strong> pentavalent antimonials = 100mg/ml.<br />
(Registered <strong>in</strong> Kenya)<br />
2. Generic sodium stibogluconate (SSG) from Albert David, Calcutta,<br />
India. Concentration <strong>of</strong> pentavalent antimonials = 100mg/ml.<br />
(Registered <strong>in</strong> Kenya)<br />
3. Glucantime® (sodium antimoniate) from San<strong>of</strong>i-Aventis, France.<br />
Concentration <strong>of</strong> pentavalent antimonials = 85mg/ml.<br />
(Registered <strong>in</strong> Kenya)<br />
For SSG the dosage is 20mg/kg/day for 30 days as a s<strong>in</strong>gle daily dose with an<br />
upper limit dose <strong>of</strong> 850mg.<br />
For Glucantime the dosage is 20mg/kg/day for 30 days as a s<strong>in</strong>gle daily dose<br />
with an upper limit dose <strong>of</strong> 850mg.<br />
They are adm<strong>in</strong>istered by <strong>in</strong>tramuscular or <strong>in</strong>travenous route. A summary <strong>of</strong><br />
treatment regimens for visceral leishmaniasis is given <strong>in</strong> Annex 8.<br />
Intravenous <strong>in</strong>jections must be adm<strong>in</strong>istered very slowly (more than 5 m<strong>in</strong>utes)<br />
<strong>and</strong> preferably through a f<strong>in</strong>e needle to avoid thrombophlebitis, <strong>and</strong> should be<br />
discont<strong>in</strong>ued immediately if cough<strong>in</strong>g, vomit<strong>in</strong>g or substantial pa<strong>in</strong> occurs.<br />
Intramuscular <strong>in</strong>jections can be very pa<strong>in</strong>ful.<br />
The weight <strong>of</strong> the patient should be taken every week <strong>and</strong> the daily dose <strong>of</strong><br />
pentavalent antimonials should be adjusted to the current weight (nearest kg).<br />
12
Patients should be checked regularly for cl<strong>in</strong>ical response. The earlier signs <strong>of</strong><br />
response are the clearance <strong>of</strong> fever (with<strong>in</strong> 3-7 days) <strong>and</strong> the improvement <strong>of</strong><br />
the general condition.<br />
Pentavalent antimonials are relatively safe but toxicity <strong>and</strong> side effects may<br />
occur. These <strong>in</strong>clude nausea, anorexia, arthralgia, myalgia, pa<strong>in</strong> at the <strong>in</strong>jection<br />
site, ECG changes, raised liver enzymes, raised pancreatic enzymes, severe<br />
vomit<strong>in</strong>g. Sudden death may occur due to cardiac arrhythmia, <strong>in</strong>tra-cerebral<br />
bleed<strong>in</strong>g, anaemia associated heart failure <strong>and</strong> renal toxicity.<br />
The risk <strong>of</strong> serious (sometimes fatal) toxicity <strong>of</strong> pentavalent antimonials is<br />
<strong>in</strong>creased <strong>in</strong> patients who concomitantly have:<br />
• Cardiac disease, <strong>in</strong> particular arrhythmias<br />
• Renal failure<br />
• Liver disease<br />
• Severe malnutrition<br />
• Very poor general condition<br />
• Advanced HIV <strong>in</strong>fection<br />
• Pregnancy<br />
If one <strong>of</strong> these conditions is present, the patient should be closely monitored or,<br />
preferably, be treated with another drug (see below).<br />
3.3.1.2 Comb<strong>in</strong>ation therapy: In this form <strong>of</strong> treatment, two or more drugs are<br />
comb<strong>in</strong>ed together to give a better efficacy <strong>and</strong> decrease the emergence <strong>of</strong><br />
resistance. The most successful comb<strong>in</strong>ation therapy currently is Sodium<br />
stibogluconate (SSG) (20 mg Sb 5 +/kg per day <strong>in</strong>tramuscularly or <strong>in</strong>travenously)<br />
plus paromomyc<strong>in</strong> (PM) ([11 mg base] (15 mg per kg) body weight per day<br />
<strong>in</strong>tramuscularly) for 17 days.<br />
NB: A Paromomyc<strong>in</strong> Drug Insert is <strong>in</strong>cluded <strong>in</strong> Annex 9.<br />
13
3.3.2.0 Second l<strong>in</strong>e VL treatment<br />
3.3.2.1 Amphoteric<strong>in</strong> B (Fungizone, Squibb).<br />
A suitable regimen is 0.75–1 mg/kg per day by <strong>in</strong>fusion, daily or on alternate<br />
days, for 15–20 doses. The major side effect <strong>of</strong> Amphoteric<strong>in</strong> B is renal<br />
impairment <strong>and</strong> renal function should preferably be monitored weekly dur<strong>in</strong>g<br />
treatment. Renal impairment can be reduced by pre-hydrat<strong>in</strong>g the patient with<br />
an <strong>in</strong>fusion <strong>of</strong> normal sal<strong>in</strong>e. If a rise <strong>in</strong> urea <strong>and</strong> creat<strong>in</strong><strong>in</strong>e occur, the <strong>in</strong>terval<br />
between doses should be lengthened. Hypokalemia <strong>and</strong> hypomagnesemia may<br />
occur <strong>and</strong> can be prevented by potassium/magnesium supplementation. Other<br />
side effects are headache, nausea, vomit<strong>in</strong>g, chills, fever, malaise, muscle <strong>and</strong><br />
jo<strong>in</strong>t pa<strong>in</strong>, diarrhoea, gastro-<strong>in</strong>test<strong>in</strong>al cramps, hypertension, hypotension,<br />
cardiac arrhythmias <strong>in</strong>clud<strong>in</strong>g ventricular fibrillation, sk<strong>in</strong> rashes, anaphylactoid<br />
reactions, blurred vision, t<strong>in</strong>nitus, hear<strong>in</strong>g loss, vertigo, liver disorders,<br />
peripheral neuropathy, convulsions, thrombophlebitis at the <strong>in</strong>jection site <strong>and</strong><br />
anaemia.<br />
Though cheaper than liposomal amphoteric<strong>in</strong> B (AmBisome®) it’s many<br />
adverse effects discourages its use <strong>in</strong> the treatment <strong>of</strong> VL.<br />
3.3.2.2 Liposomal Amphoteric<strong>in</strong> B (AmBisome®)<br />
AmBisome comes <strong>in</strong> vials <strong>of</strong> 50 mg <strong>and</strong> needs to be reconstituted <strong>and</strong> diluted <strong>in</strong><br />
5% Dextrose <strong>and</strong> given over a period 30 - 60 m<strong>in</strong>utes as an <strong>in</strong>travenous<br />
<strong>in</strong>fusion. The recommended dose <strong>in</strong> Kenya is 3-5mg/kg body weight per daily<br />
dose by <strong>in</strong>fusion given over six to ten days up to a total dose <strong>of</strong> 30mg/kg.<br />
Note: Do NOT dilute with sal<strong>in</strong>e solutions or mixed with other electrolytes or<br />
drugs.<br />
AmBisome is not registered <strong>in</strong> Kenya at the moment.<br />
Storage conditions:<br />
Prior to usage, AmBisome should be stored at 2°- 8°C <strong>and</strong> should not be<br />
frozen. It should also be protected from exposure to light.<br />
The reconstituted AmBisome may be stored for 15-24 hours at 2°- 8°C<br />
before use.<br />
14
Side effects:<br />
Are rare but the patient may have fever, chills <strong>and</strong> a low backache if the<br />
<strong>in</strong>fusion is given too fast. Anaphylactoid reactions have also been<br />
observed <strong>in</strong> some patients.<br />
Hypokalaemia may occur <strong>in</strong> some patients <strong>and</strong> should be corrected us<strong>in</strong>g<br />
potassium chloride.<br />
Pregnancy <strong>and</strong> the neonate:<br />
There are no reports <strong>of</strong> pregnant woman hav<strong>in</strong>g been treated with<br />
AmBisome. Therefore, AmBisome should be used dur<strong>in</strong>g pregnancy only<br />
after weigh<strong>in</strong>g the risks versus the benefit <strong>of</strong> treatment.<br />
Contra <strong>in</strong>dications:<br />
AmBisome is contra <strong>in</strong>dicated <strong>in</strong> patients who have experienced previous<br />
hypersensitivity reactions.<br />
Note: Although AmBisome is more expensive compared to conventional<br />
Amphoteric<strong>in</strong> B it is recommended as a second l<strong>in</strong>e treatment due to it’s<br />
relatively fewer adverse effects.<br />
3.3.3 Def<strong>in</strong>itions <strong>of</strong> Treatment Outcomes <strong>in</strong> VL<br />
Non responder: A patient who shows no or poor cl<strong>in</strong>ical response after 30 days<br />
<strong>of</strong> pentavalent antimonials or 17 days <strong>of</strong> comb<strong>in</strong>ation (SSG + PM) treatment<br />
<strong>and</strong> presents with a parasitological smear show<strong>in</strong>g parasite density equal or<br />
greater than before treatment.<br />
Slow responder: A patient who shows m<strong>in</strong>imal cl<strong>in</strong>ical response after 30 days<br />
<strong>of</strong> pentavalent antimonials or 17 days <strong>of</strong> comb<strong>in</strong>ation (SSG + PM) treatment<br />
<strong>and</strong> presents with a parasitological smear less than before treatment but is still<br />
positive. If after a second course <strong>of</strong> treatment, such a patient is still<br />
parasitologically positive (even 1+), he is considered as a non responder.<br />
Relapse case: A patient who successfully completes a course <strong>of</strong> st<strong>and</strong>ard VL<br />
treatment <strong>and</strong> shows evidence <strong>of</strong> cl<strong>in</strong>ical <strong>and</strong> parasitological response (negative<br />
15
test <strong>of</strong> cure) but presents with cl<strong>in</strong>ical <strong>and</strong> parasitological evidence <strong>of</strong> VL with<strong>in</strong><br />
6 months <strong>of</strong> completion therapy.<br />
Drug resistant case: A VL patient with a laboratory confirmed drug resistant<br />
parasite.<br />
Test <strong>of</strong> Cure (TOC): Test<strong>in</strong>g for presence or absence <strong>of</strong> amastigotes <strong>in</strong> a VL<br />
patient at end <strong>of</strong> treatment. Negative TOC is absence <strong>of</strong> amastigotes <strong>in</strong> a tissue<br />
slide taken from a VL patient at the end <strong>of</strong> treatment. A positive TOC is<br />
presence <strong>of</strong> amastigotes <strong>in</strong> a tissue slide taken from a VL patient at the end <strong>of</strong><br />
treatment.<br />
Def<strong>in</strong>itive Cure: A VL patient who has received treatment for VL <strong>and</strong> has a<br />
negative parasitological slide at 6 months after treatment.<br />
Criteria for cure<br />
In health facilities that cannot carry out parasitological test to determ<strong>in</strong>e test <strong>of</strong><br />
cure, the follow<strong>in</strong>g criteria should be used to decide cl<strong>in</strong>ical cure from the<br />
disease:<br />
� Return <strong>of</strong> normal appetite<br />
� No fever<br />
� Regression <strong>of</strong> spleen<br />
� Improvement <strong>in</strong> anaemia <strong>and</strong> a rise <strong>in</strong> haemoglob<strong>in</strong> level<br />
� Increase <strong>in</strong> WBC<br />
� The full course <strong>of</strong> treatment has been adm<strong>in</strong>istered<br />
� Increase <strong>in</strong> body weight<br />
In this case, the patient should be requested to come for a follow up after 60<br />
days.<br />
16
3.3.4. Drugs used <strong>in</strong> the treatment <strong>of</strong> relapses <strong>and</strong> non-responsiveness <strong>of</strong><br />
visceral leishmaniasis.<br />
Drugs which can been used <strong>in</strong> repeated relapses <strong>and</strong> unresponsive cases <strong>in</strong>clude:<br />
1. Liposomal Amphoteric<strong>in</strong> B (AmBisome®), total dose 3-<br />
5mg/kg/day for 6 to 10 days as an <strong>in</strong>travenous <strong>in</strong>fusions given<br />
slowly for 30-60 m<strong>in</strong>utes.<br />
2. Amphoteric<strong>in</strong> B (Fungizone, Squibb). 0.75–1 mg/kg per day by<br />
<strong>in</strong>fusion, daily or on alternate days, for 15–20 doses<br />
3. Pentavalent antimonials 20mg/kg/day for 30 days + allopur<strong>in</strong>ol at<br />
7mg/kg thrice a day orally. Allopur<strong>in</strong>ol must be taken with plenty<br />
<strong>of</strong> fluids.<br />
If pentavalent antimonials are the only available drugs, 20mg/kg/day can be<br />
given for a total <strong>of</strong> 60-90 days.<br />
3.3.5 Drugs under cl<strong>in</strong>ical evaluation<br />
Patients with VL need an oral, safe, effective, low cost, short course treatment.<br />
There is also a need to further improve po<strong>in</strong>t <strong>of</strong> care diagnosis tools that are<br />
field adapted. Towards this end, the M<strong>in</strong>istry is collaborat<strong>in</strong>g with research<br />
<strong>in</strong>stitutions <strong>and</strong> <strong>in</strong>ternational research organizations e.g. KEMRI, DNDi, MSF<br />
<strong>and</strong> others. Through such collaborations, specialized VL treatment centres that<br />
<strong>of</strong>fer specialized care have been established. They <strong>of</strong>fer the community a<br />
chance to participate <strong>in</strong> research <strong>in</strong> order to improve diagnosis <strong>and</strong> treatment <strong>of</strong><br />
VL.<br />
The drugs currently under evaluation are:<br />
1. Miltefos<strong>in</strong>e (alone)<br />
2. Comb<strong>in</strong>ation: (Miltefos<strong>in</strong>e + AmBisome)<br />
3. Comb<strong>in</strong>ation: (AmBisome + SSG)<br />
3.3.6 Anti-leishmanial drugs used <strong>in</strong> other countries<br />
Miltefos<strong>in</strong>e (Impavido®, Zentaris Pharma, Canada) was <strong>in</strong>itially developed as<br />
an anti-cancer drug. Currently it is an oral drug for VL. Miltefos<strong>in</strong>e has some<br />
undesirable adverse effects such as teratogenicity, diarrhoea <strong>and</strong> vomit<strong>in</strong>g<br />
necessitat<strong>in</strong>g anti-emetics <strong>and</strong> anti-nausea. Miltefos<strong>in</strong>e use is strictly<br />
17
contra<strong>in</strong>dicated <strong>in</strong> pregnant women or <strong>in</strong> women who could become pregnant<br />
with<strong>in</strong> 3 months after treatment.<br />
3.4 VL <strong>and</strong> HIV co-<strong>in</strong>fection<br />
S<strong>in</strong>ce both VL <strong>and</strong> HIV attack the immune system <strong>of</strong> the body they produce a<br />
pr<strong>of</strong>ound immune deficiency state. The results <strong>and</strong> effect <strong>of</strong> this state is that VL<br />
accelerates the onset <strong>of</strong> full-blown AIDS <strong>and</strong> shortens the life expectancy <strong>of</strong><br />
HIV-<strong>in</strong>fected people, while HIV complicates management <strong>of</strong> VL. WHO also<br />
classifies VL as a stage 4 HIV def<strong>in</strong><strong>in</strong>g illness. VL lowers the Total<br />
Lymphocyte Count (TLC) <strong>and</strong> CD4 count to a great extent by depress<strong>in</strong>g the<br />
bone marrow <strong>and</strong> the splenic activities.<br />
The best long-term prospects will exist if a patient with HIV/VL is started on<br />
ART after VL treatment. As well as attempt<strong>in</strong>g to cure VL, important secondary<br />
objectives for HIV/VL co-<strong>in</strong>fected patients are counsell<strong>in</strong>g <strong>and</strong> psychosocial<br />
support, relief <strong>of</strong> symptoms, treatment <strong>of</strong> secondary <strong>in</strong>fections <strong>and</strong><br />
prevention/treatment <strong>of</strong> opportunistic <strong>in</strong>fections.<br />
The special difficulties with VL co-<strong>in</strong>fection <strong>in</strong>clude anaemia, bleed<strong>in</strong>g,<br />
malnutrition <strong>and</strong> concurrent illnesses. Patients with HIV can get severe<br />
diarrhoea <strong>and</strong> vomit<strong>in</strong>g. These should be aggressively diagnosed <strong>and</strong> treated.<br />
Patients with VL-HIV co <strong>in</strong>fection should not be treated with antimonial<br />
compounds unless the benefits outweigh the risk. AmBisome® is the first-l<strong>in</strong>e<br />
drug <strong>of</strong> choice <strong>in</strong> these patients <strong>and</strong> may require higher total dose. If this drug is<br />
not available, conventional Amphoteric<strong>in</strong> B® is a suitable alternative. All VL-<br />
HIV patients with VL should be classified as WHO stage IV AIDS def<strong>in</strong><strong>in</strong>g<br />
disease <strong>and</strong> should receive Highly Active Anti Retroviral Therapy (HAART).<br />
(WHO Informal Consultative Meet<strong>in</strong>g on HIV VL co-<strong>in</strong>fections March 2007,<br />
Addis Ababa).<br />
Other concomitant <strong>in</strong>fections such as TB, c<strong>and</strong>idiasias, pneumonia, <strong>and</strong><br />
diarrhoea should all be diagnosed <strong>and</strong> treated appropriately. VL relapses <strong>and</strong><br />
mortality are more common <strong>in</strong> HIV co-<strong>in</strong>fected patients.<br />
Note that a def<strong>in</strong>itive cure cannot be achieved by any drug, <strong>and</strong> relapse is almost<br />
18
<strong>in</strong>evitable. The time to relapse is usually 3 - 6 months, with successive relapses<br />
becom<strong>in</strong>g less typical <strong>and</strong> less acute, but occurr<strong>in</strong>g more frequently.<br />
Patients are less responsive to treatment with each relapse, <strong>and</strong> eventually may<br />
become unresponsive to all drugs used. With repeated courses <strong>of</strong> antileishmanials,<br />
parasite stra<strong>in</strong>s become progressively less sensitive to the drug<br />
<strong>and</strong> toxicity may eventually outweigh the benefits. Therefore patients with VL<br />
who get 2 or more relapses an HIV test should be done.<br />
3.5.0 Post <strong>Kala</strong> <strong>Azar</strong> Dermal Leishmaniasis (PKDL)<br />
3.5.1 Prevalence<br />
In Kenya PKDL occurs dur<strong>in</strong>g the first few months after complet<strong>in</strong>g treatment<br />
with a prevalence <strong>of</strong> 2-5% <strong>of</strong> treated cases. However a few cases have been<br />
noted dur<strong>in</strong>g treatment. PKDL cases are thought to be the ma<strong>in</strong> reservoir <strong>of</strong><br />
<strong>in</strong>fection dur<strong>in</strong>g <strong>in</strong>ter-epidemic periods <strong>and</strong> some cases give no history <strong>of</strong><br />
previous VL disease. So identification <strong>of</strong> PKDL cases is relevant so as to reduce<br />
the human reservoir pool <strong>of</strong> the disease.<br />
3.5.2 Presentation<br />
The most common presentation <strong>of</strong> PKDL is hypo-pigmented macules or papules<br />
on the face. The lesions can become nodular <strong>and</strong> spread to the limbs <strong>and</strong> trunk.<br />
The lesions are non-itchy <strong>and</strong> are symmetrical.<br />
3.5.3 <strong>Diagnosis</strong><br />
Suspected PKDL cases should undergo 2 sk<strong>in</strong> slit smears <strong>of</strong> the lesions to<br />
confirm diagnosis. Sta<strong>in</strong><strong>in</strong>g procedure is same as for splenic aspirate smear.<br />
(Annexes 1, 2, 3 <strong>and</strong> 4)<br />
3.5.4 Treatment<br />
Confirmed PKDL cases should receive the same treatment as for VL. PKDL<br />
cases respond well to antimony drugs but require longer duration <strong>of</strong> treatment.<br />
Treatment should cont<strong>in</strong>ue for 30 days. If there is no parasitological cure (sk<strong>in</strong><br />
slit smears still positive) give additional 30 days <strong>of</strong> pentavalent antimonials.<br />
However, difficult cases require addition <strong>of</strong> allopur<strong>in</strong>ol at 7mg/kg three times a<br />
day orally.<br />
19
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test test <strong>and</strong> KAtex <strong>in</strong> East Africa <strong>and</strong> the Indian subcont<strong>in</strong>ent. Trans.<br />
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<strong>of</strong> Leishmania Donovani <strong>in</strong> Smears <strong>of</strong> Splenic Aspirates from Patients<br />
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Koummuki Y, Rashid J, Mbui J, Mucee G, Njoroge S, M<strong>and</strong>uku V,<br />
Musibi A, Mutuma G, Kirui F, Lodenyo H, Mutea D, Kirigi G, Edwards<br />
T, Smith P, Muthami L, Royce C, Ellis E, Alobo A, Omollo R, Kesusu J,<br />
Owiti R, K<strong>in</strong>uthia J, for the Leishmaniasis East Africa Platform (LEAP)<br />
group (2010). Geographical Variation <strong>in</strong> the Response <strong>of</strong> Visceral<br />
Leishmaniasis to Paromomyc<strong>in</strong> <strong>in</strong> East Africa: A Multicentre, Open-<br />
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Robert, De La Tour, Joke, P., Lausermayer, A., Omollo, R., Balasegaram,<br />
M., Chappuis F. (2011). Validation <strong>of</strong> Two Rapid Tests for <strong>Diagnosis</strong> <strong>of</strong><br />
Visceral Leishmaniasis <strong>in</strong> Kenya (Poster presentation at the 7 th European<br />
Congress on Tropical Medic<strong>in</strong>e & International Health).<br />
6. M<strong>in</strong>istry <strong>of</strong> Health Federal Democratic Republic <strong>of</strong> Ethiopia, (2006).<br />
Visceral Leishmaniasis – <strong>Diagnosis</strong> & Treatment for Health Workers <strong>in</strong><br />
Ethiopia 1 st Edition. Unpublished Manuscript<br />
7. M<strong>in</strong>istry <strong>of</strong> Health Federal M<strong>in</strong>istry <strong>of</strong> Health - Sudan, (2005). Manual<br />
for <strong>Diagnosis</strong> <strong>and</strong> Treatment <strong>of</strong> Leishmaniasis. Unpublished Manuscript<br />
8. M<strong>in</strong>istry <strong>of</strong> Health - Ug<strong>and</strong>a, (2007). <strong>Diagnosis</strong> <strong>and</strong> Treatment <strong>of</strong><br />
Visceral Leishmaniasis <strong>in</strong> Ug<strong>and</strong>a 2 nd Draft. Unpublished Manuscript<br />
9. M<strong>in</strong>istry <strong>of</strong> Public Health <strong>and</strong> Sanitation Kenya. National Multi-Year<br />
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Strategic Plan for Control <strong>of</strong> Neglected Tropical Diseases (2011-2015)<br />
10. Musa AM, Younis B, Fadlalla A, Royce C, Balasegaram M, Wasunna M,<br />
Hailu A, Edwards T, Omollo R, Mudawi M, Kokwaro G, El-Hassan A,<br />
Khalil E (2010). Paromomyc<strong>in</strong> for the Treatment <strong>of</strong> Visceral<br />
Leishmaniasis <strong>in</strong> Sudan: A R<strong>and</strong>omized, Open-Label, Dose-F<strong>in</strong>d<strong>in</strong>g<br />
Study.<br />
PLoS Negl Trop Dis 4(10): e855.doi:10.1371/journal.pntd.0000855<br />
11. WHO (2002). New Therapy for Visceral Leishmaniasis. Weekly<br />
Epidemiological Record No. 25Pg 210 – 212<br />
12. WHO Informal Consultative Meet<strong>in</strong>g on HIV VL co-<strong>in</strong>fections March<br />
2007. Addis Ababa.<br />
13. Mebrahtu Y; Lawyer P; Githure J; Kager P; Leeuwenburg J; Perk<strong>in</strong>s P;<br />
Oster C. <strong>and</strong> Hendricks L.D. Indigenous human cutaneous leishmaniasis<br />
caused by Leishmania tropica <strong>in</strong> Kenya. American Journal <strong>of</strong> Tropical<br />
Medic<strong>in</strong>e <strong>and</strong> Hygiene 1988; 39(3): 267-73.<br />
14. Mebrahtu Y; Oster CN; Shatry AM; Hendricks LD; Githure JI; Rees PH;<br />
Perk<strong>in</strong>s P. <strong>and</strong> Leeuwenburg J. Cutaneous leishmaniasis caused by<br />
Leishmania tropica <strong>in</strong> Kenya. Transactions <strong>of</strong> the Royal Society for<br />
Tropical Medic<strong>in</strong>e <strong>and</strong> Hygiene 1987; 81: 923-924<br />
15. Mercè Herrero. Visceral Leishmaniasis outbreak <strong>in</strong> Wajir district, Kenya.<br />
WHO Assessment report, 2008<br />
16. Michela Pelizzi, Marta Verna, Maurizio Vanelli (2006). A case report <strong>of</strong><br />
visceral leishmaniasis <strong>in</strong> the Tharaka ACTA BIOMED 2006; 77; 103-105<br />
17. Wijers D.J, Kiilu G. Studies on the vectors <strong>of</strong> <strong>Kala</strong> azar <strong>in</strong> Kenya, VIII.<br />
The outbreak <strong>in</strong> Machakos District: Epidemiological features <strong>and</strong><br />
possible way <strong>of</strong> control. Ann. Trop. Med. Parasitol 1984;78: 597-604<br />
18. WHO Technical Report Series 949: Control <strong>of</strong> Leishmaniases. Report <strong>of</strong><br />
a meet<strong>in</strong>g <strong>of</strong> the WHO Expert Committee on the Control <strong>of</strong><br />
Leishmanaises, Geneva, 22-26 March 2010.<br />
21
Annex 1: Guidel<strong>in</strong>e for Splenic Aspiration<br />
The follow<strong>in</strong>g requirement must be met before splenic aspiration can be done:<br />
1. Splenomegaly must be present <strong>in</strong> a patient cl<strong>in</strong>ically suspected <strong>of</strong> visceral<br />
leishmaniasis (VL)<br />
2. Haemoglob<strong>in</strong> <strong>of</strong> ≥5gm/dl.<br />
3. Platelet count <strong>of</strong> ≥40,000/mm 3<br />
4. White Blood cell count <strong>of</strong> at least ≥1.0 x 10 3 /mm 3<br />
5. A prothromb<strong>in</strong> time difference <strong>of</strong> not more than 5 second compared with<br />
the normal control.<br />
6. The patient should not have had a splenic aspiration with<strong>in</strong> one week<br />
from the date <strong>of</strong> the current procedure.<br />
7. No active bleed<strong>in</strong>g.<br />
8. No cl<strong>in</strong>ical jaundice (a possible marker <strong>of</strong> liver dysfunction).<br />
9. No pregnancy.<br />
Splenic Aspiration Procedure<br />
• In patients less than 5 year old, splenic aspiration should be<br />
performed only by a cl<strong>in</strong>ician fully experienced with the procedure<br />
otherwise bone marrow is recommended from the iliac crest.<br />
• A patient is made to lie <strong>in</strong> the sup<strong>in</strong>e position with h<strong>and</strong>s on the<br />
sides.<br />
• The edge <strong>of</strong> the spleen is outl<strong>in</strong>ed with a ball pen.<br />
• The area <strong>of</strong> the spleen is cleaned by the cl<strong>in</strong>ician us<strong>in</strong>g spirit or any<br />
other antiseptic <strong>and</strong> a green towel (sterile, like the one used for<br />
bone marrow aspirates) placed over the splenic area.<br />
• A 21 gauge needle attached to a 5 ml syr<strong>in</strong>ge is <strong>in</strong>serted just under<br />
the sk<strong>in</strong> over the middle <strong>of</strong> the spleen, <strong>and</strong> as suction is applied<br />
(about 1 ml) the needle is rapidly <strong>in</strong>serted <strong>in</strong>to the spleen <strong>and</strong><br />
withdrawn, with the needle rema<strong>in</strong><strong>in</strong>g <strong>in</strong> the spleen only a fraction<br />
<strong>of</strong> a second.<br />
• The small amount <strong>of</strong> splenic tissue <strong>and</strong> blood <strong>in</strong> the needle is<br />
expressed <strong>in</strong>to the culture medium (NNN) or Schneider’s with 10%<br />
overlay <strong>of</strong> fetal calf serum) <strong>and</strong> onto slides for the smears.<br />
22
• The splenic smears are sta<strong>in</strong>ed with Giemsa or Leishman<strong>in</strong> sta<strong>in</strong> to<br />
demonstrate amastigotes.<br />
NB: Bone marrow aspirate may be done but usually bone marrow smears<br />
conta<strong>in</strong> fewer amastigotes <strong>and</strong> parasites are found <strong>in</strong> only 80 –85% <strong>of</strong> cases.<br />
The procedure should be h<strong>and</strong>led under sterile conditions <strong>and</strong> therefore this<br />
must be observed by the attend<strong>in</strong>g cl<strong>in</strong>ician.<br />
Instructions after the Splenic Aspirate<br />
1. Patient to stay <strong>in</strong> bed strictly for 12 hours.<br />
2. Observe Blood Pressure, Pulse, Temperature, <strong>and</strong> Respiratory Rate<br />
immediately after the aspiration then ½ hourly for 2 hours, 1 hourly<br />
for 4 hours then 4 hourly.<br />
3. Suspect bleed<strong>in</strong>g if there is fall<strong>in</strong>g Blood Pressure, ris<strong>in</strong>g Pulse <strong>and</strong><br />
normal or fall<strong>in</strong>g Temperature; fix an IV l<strong>in</strong>e immediately <strong>of</strong> 5%<br />
dextrose alternat<strong>in</strong>g with normal sal<strong>in</strong>e. Take Blood for group<strong>in</strong>g<br />
<strong>and</strong> cross match<strong>in</strong>g immediately. Usually majority <strong>of</strong> the patients<br />
settle with IV fluids <strong>in</strong>fusion with<strong>in</strong> 12 hours.<br />
4. Repeat aspiration should only be done after one week <strong>and</strong> not<br />
earlier.<br />
23
Annex 2: Guidel<strong>in</strong>e on Bone Marrow Aspiration<br />
1. Place the patient <strong>in</strong> a right or left lateral decubitus position with the<br />
back comfortably flexed <strong>and</strong> the top knee drawn toward the chest.<br />
2. Locate the posterior iliac sp<strong>in</strong>e <strong>and</strong> mark with <strong>in</strong>k or thumb nail<br />
pressure<br />
3. Us<strong>in</strong>g sterile technique, prepare the sk<strong>in</strong> with anti-septics <strong>and</strong><br />
drape<br />
4. Us<strong>in</strong>g sterile syr<strong>in</strong>ge, apply/<strong>in</strong>filtrate the marked area with<br />
anaesthetic especially the periosteum<br />
5. Make a 3-mm sk<strong>in</strong> <strong>in</strong>cision with a scalpel blade over the marked<br />
area.<br />
6. Hold the needle with the proximal end <strong>in</strong> the palm <strong>and</strong> the <strong>in</strong>dex<br />
f<strong>in</strong>ger aga<strong>in</strong>st the shaft near the tip.<br />
7. With the stylet locked <strong>in</strong> place, <strong>in</strong>troduce the needle through the<br />
<strong>in</strong>cision po<strong>in</strong>t<strong>in</strong>g toward the anterior superior iliac sp<strong>in</strong>e <strong>and</strong> br<strong>in</strong>g<br />
it <strong>in</strong>to contact with the posterior iliac sp<strong>in</strong>e<br />
8. Us<strong>in</strong>g gentle but firm pressure, advance the needle to bore through<br />
the iliac sp<strong>in</strong>e<br />
9. Rotate the needle <strong>in</strong> an alternat<strong>in</strong>g clock-wise <strong>and</strong> counter-<br />
clockwise motion. Entrance <strong>in</strong>to the marrow cavity is generally<br />
detected by decreased resistance.<br />
10. Remove the stylet, <strong>and</strong> check for presence/absence <strong>of</strong> marrow<br />
material. If not, proceed gently to bore until marrow is found at the<br />
tip <strong>of</strong> the stylet.<br />
11. Us<strong>in</strong>g a 10cc syr<strong>in</strong>ge, locked <strong>in</strong>to the proximal portion <strong>of</strong> the bone<br />
marrow needle aspirate for bone marrow material.<br />
12. The material can then be expelled onto a clean slide. Presence <strong>of</strong><br />
bone marrow material can be detected as granules on a glass slide.<br />
24
Annex 3: Preparation <strong>and</strong> Sta<strong>in</strong><strong>in</strong>g <strong>of</strong> Aspirates<br />
Materials needed<br />
Slides rack, sta<strong>in</strong><strong>in</strong>g rack or sta<strong>in</strong><strong>in</strong>g trough, 100% methanol, <strong>and</strong> filtered stock<br />
<strong>of</strong> Giemsa sta<strong>in</strong><br />
Fixation<br />
• Place the slides horizontally on the slide rack <strong>and</strong> leave to air dry.<br />
• Fix the slides by dipp<strong>in</strong>g them <strong>in</strong> 100% methanol for l m<strong>in</strong>ute. The<br />
methanol must be stored <strong>in</strong> a tightly closed bottle to prevent<br />
absorption <strong>of</strong> water.<br />
Sta<strong>in</strong><strong>in</strong>g<br />
• Sta<strong>in</strong> the slides with Giemsa sta<strong>in</strong> 1:10 concentration; 1 ml <strong>of</strong> stock<br />
Giemsa sta<strong>in</strong> to 9ml buffer solution pH 7.2. In the absence <strong>of</strong> buffer<br />
solution, filtered water can be used provided the pH is 7.2. The slides can<br />
either be sta<strong>in</strong>ed <strong>in</strong> a sta<strong>in</strong><strong>in</strong>g trough or on a sta<strong>in</strong><strong>in</strong>g rack. When the sta<strong>in</strong><br />
concentration is 1:10 the sta<strong>in</strong><strong>in</strong>g time is 20m<strong>in</strong>utes.<br />
• At the end <strong>of</strong> the sta<strong>in</strong><strong>in</strong>g, r<strong>in</strong>se the slides briefly with tap water or<br />
filtered water <strong>and</strong> place them <strong>in</strong> vertical position on a slides rack to dry.<br />
Read<strong>in</strong>g Slides:<br />
• Exam<strong>in</strong>e at least 1000 microscope fields for amastigotes us<strong>in</strong>g X100<br />
oil immersion lens. It takes at least 20 m<strong>in</strong>utes or 1000 microscope<br />
fields <strong>of</strong> read<strong>in</strong>g a slide to declare it as negative. An artefact is more<br />
likely to be mistaken for a parasite if the microscopists are overloaded<br />
(more than 4 hours <strong>of</strong> microscopy per day), have poor light for the<br />
microscopes, or if dirty (unfiltered) Giemsa is used.<br />
25
Annex 4: Grad<strong>in</strong>g <strong>of</strong> Splenic Aspirate Smears for Leishmania<br />
Amastigotes<br />
Grad<strong>in</strong>g <strong>of</strong> the number <strong>of</strong> Leishmania amastigotes <strong>in</strong> splenic aspirate smears<br />
Logarithmic<br />
Grade<br />
Number <strong>of</strong><br />
Parasites<br />
0 0 1000<br />
1+ 1 -10 1000<br />
2+ 1 -10 100<br />
3+ 1 -10 10<br />
4+ 1 -10 1<br />
5+ 10-100 1<br />
6+ >100 1<br />
26<br />
Microscopic<br />
Fields<br />
Plate A: Splenic aspirate smear show<strong>in</strong>g Leishmania donovani amastigotes
Plate B: Splenic aspirate smear show<strong>in</strong>g Leishmania donovani amastigotes<br />
27
Annex 5: Direct Agglut<strong>in</strong>ation Test (DAT)<br />
Blood can be collected from the f<strong>in</strong>ger to blot on to filter paper (Whatman No.3)<br />
or from the ve<strong>in</strong> to obta<strong>in</strong> serum or plasma. Serial dilutions <strong>of</strong> the patient’s<br />
blood sample eluted from filter paper, or directly from serum, is <strong>in</strong>cubated with<br />
Leishmania antigen <strong>in</strong> V-shaped microtitre plates. The plates are <strong>in</strong>cubated at<br />
room temperature for 8-12 hours <strong>and</strong> then read visually. If no anti-Leishmania<br />
antibodies are present, the antigen will sediment to the bottom <strong>of</strong> the well <strong>and</strong><br />
form a small sharp blue dot. If anti-Leishmania antibodies are present <strong>in</strong> the<br />
blood, they will react with the antigen <strong>and</strong> the agglut<strong>in</strong>ation will be visible as a<br />
blue mat, a dot with frayed edges, or an enlarged dot.<br />
1, Materials<br />
Freeze dried Leishmania antigen (FD)<br />
Phosphate Buffered Sal<strong>in</strong>e (PBS) pH 7.2 or normal sal<strong>in</strong>e<br />
Gelat<strong>in</strong> powder<br />
2-mercaptoethanol (2-ME)<br />
Micro-titre plates V-shaped with self adhesive sealers or covers<br />
1µl pipette<br />
50µl pipette<br />
50µl multi-channel pipette<br />
100µl multi-channel pipette<br />
Disposable tips for pipettes<br />
Negative <strong>and</strong> positive serum samples<br />
2, Serum diluent<br />
Normal sal<strong>in</strong>e solution or PBS conta<strong>in</strong><strong>in</strong>g 0.2% gelat<strong>in</strong><br />
Sodium nitrite could be added to the buffer as a preservative (Optional)<br />
Prepare fresh serum diluents every time the test is done <strong>and</strong> add 2-ME to make<br />
a 0.78%<br />
NB. Take care when h<strong>and</strong>l<strong>in</strong>g 2-mercaptoethanol as it is a toxic substance<br />
28
Test Procedure<br />
1. Dispense 50µl <strong>of</strong> SD <strong>in</strong>to all the wells except column 2 where you<br />
dispense 100µl <strong>of</strong> sample diluent<br />
2. Add 1µl <strong>of</strong> either test or control serum samples <strong>in</strong>to column 2 (A-<br />
H)<br />
Serum dilutions<br />
1. Us<strong>in</strong>g a multi-channel pipette mix column 2 thoroughly <strong>and</strong><br />
transfer 50µl from column 2 to column 3, mix thoroughly <strong>and</strong><br />
transfer 50µl from column 3 to column 4, repeat this until<br />
column12 (giv<strong>in</strong>g a dilution <strong>of</strong> 1:102,400) <strong>and</strong> discard the last 50µl<br />
Column 2 is used as the FD antigen control s<strong>in</strong>ce it conta<strong>in</strong>s only<br />
the antigen <strong>and</strong> the sample diluents. Any auto-agglut<strong>in</strong>ation <strong>of</strong> the<br />
antigen will be seen <strong>in</strong> this row.<br />
2. Add 50µl <strong>of</strong> antigen suspension <strong>in</strong> each <strong>and</strong> every well <strong>of</strong> the plate<br />
us<strong>in</strong>g a multi-channel dispenser pipette<br />
3. Cover the plates <strong>and</strong> rotate the plate gently by h<strong>and</strong> for one m<strong>in</strong>ute<br />
by swirl<strong>in</strong>g.<br />
4. Leave the plates on an equal level surface <strong>and</strong> let <strong>in</strong>cubate<br />
overnight at room temperature<br />
Read<strong>in</strong>g the plates<br />
1. Put the plates on a white background <strong>and</strong> determ<strong>in</strong>e the titre by<br />
compar<strong>in</strong>g the agglut<strong>in</strong>ation button to the control <strong>in</strong> column 1<br />
2. The titre is the highest dilution <strong>of</strong> the serum sample that gives a<br />
positive reaction <strong>and</strong> it is usually a well before that which is<br />
identical to the antigen control.<br />
NB. Once reconstituted, the antigen should be stored at 4 0 C for not more<br />
than 1 week<br />
29
Serial two fold dilutions (start<strong>in</strong>g 1:100) from the serum samples are made <strong>in</strong> a<br />
V-shaped micro titre plate. The antigen is added <strong>and</strong> the plates are read the next<br />
day. Agglut<strong>in</strong>ation is visible as a blue/purple mat <strong>in</strong> the wells <strong>of</strong> the micro titre<br />
plate. Serum is diluted from row A to row G;Row H is used as negative<br />
control.<br />
Interpretation <strong>of</strong> DAT Results<br />
DAT positive patients (patients with titres <strong>of</strong> 1:12,800 <strong>and</strong> above) are sent for<br />
admission <strong>and</strong> further parasitological <strong>in</strong>vestigations carried out<br />
DAT negative patients (patients with titres below 1:12800) are evaluated for<br />
other diseases <strong>and</strong> told to return for repeat DAT after 2 - 3 weeks if they still<br />
feel sick. By then their titre might have risen if they have VL.<br />
DAT borderl<strong>in</strong>e patients (patients with titres <strong>of</strong> 1:6400 <strong>and</strong> 1:12800) are either<br />
evaluated for other diseases or told to return for repeat DAT after 1 - 2 weeks,<br />
or they are admitted for parasitological <strong>in</strong>vestigations.<br />
30<br />
A<br />
B<br />
C<br />
D<br />
E<br />
F<br />
G<br />
H
If the results <strong>of</strong> two successive splenic, or bone marrow aspirates are all<br />
negative, they are treated for other diseases.<br />
NB. Due to the batch to batch variations <strong>of</strong> DAT antigens, it is necessary to<br />
make adjustments to the cut-<strong>of</strong>f value. VL control programs should ensure<br />
that DAT antigen <strong>of</strong> acceptable quality is procured (from KIT)<br />
Important rem<strong>in</strong>ders about the DAT<br />
The DAT does not dist<strong>in</strong>guish between exposure, previously treated cases <strong>of</strong><br />
VL <strong>and</strong> active VL as the antibodies rema<strong>in</strong> <strong>in</strong> the blood for a number <strong>of</strong> years<br />
(up to 10 or more years) after successful treatment. Therefore, DAT is not<br />
useful for diagnos<strong>in</strong>g relapses <strong>and</strong> is substituted by parasitological test like the<br />
splenic aspirates.<br />
31
Annex 6a: A diagram illustrat<strong>in</strong>g the steps for perform<strong>in</strong>g the rk39 rapid<br />
diagnostic test<br />
(Adapted from WHO Technical Report series 949)<br />
32
Annex 6b: <strong>in</strong>terpretation <strong>of</strong> rK39 rapid diagnostic test results<br />
Test read<strong>in</strong>g:<br />
Positive result<br />
The test is positive if both the control <strong>and</strong> test l<strong>in</strong>es appear. It implies that the<br />
sample tested has antibodies aga<strong>in</strong>st recomb<strong>in</strong>ant K39 antigen <strong>of</strong> Leishmania.<br />
Even a fa<strong>in</strong>t l<strong>in</strong>e should be considered as a positive result.<br />
Negative result<br />
The test is considered negative if only the control l<strong>in</strong>e appears. It means there<br />
are no antibodies aga<strong>in</strong>st recomb<strong>in</strong>ant rK39 antigen <strong>of</strong> Leishmania present<br />
<strong>in</strong> the patient’s sample.<br />
Invalid result<br />
The test is considered <strong>in</strong>valid if no control l<strong>in</strong>e appears whether the test l<strong>in</strong>e<br />
appears or not. In such situation, retest<strong>in</strong>g a fresh patient sample with a new<br />
strip is recommended.<br />
How is the test <strong>in</strong>terpreted?<br />
The rK39 test stays positive <strong>in</strong> VL patients for a long time after treatment (past<br />
VL), <strong>and</strong> the dipstick can also be positive <strong>in</strong> healthy persons from endemic<br />
areas who are <strong>in</strong>fected with Leishmania but not sick. Therefore the test cannot<br />
33
e used as a st<strong>and</strong>-alone test. The test can only be <strong>in</strong>terpreted mean<strong>in</strong>gfully <strong>in</strong><br />
people who are cl<strong>in</strong>ically suspect for VL, hav<strong>in</strong>g a first-time episode.<br />
To whom the rK39 dipstick should be applied<br />
• Persons from endemic areas who are cl<strong>in</strong>ically suspect for VL: fever for<br />
more than 2 weeks <strong>and</strong> enlarged spleen or wast<strong>in</strong>g.<br />
NB. The rapid diagnostic test should be used to confirm <strong>Kala</strong> azar when the<br />
patient’s symptoms match the case def<strong>in</strong>ition – not to rule it out.<br />
To whom the rK39 dipstick should not be applied<br />
• Persons with past VL history<br />
• In HIV-VL co-<strong>in</strong>fected persons<br />
34
Annex 7: Visceral leishmaniasis diagnostic algorithm<br />
Treatment<br />
for relapse<br />
Visceral leishmaniasis diagnostic algorithm<br />
Previous VL case<br />
Spleen aspirate<br />
+ -<br />
Non kala-azar<br />
→ search other<br />
diagnosis<br />
<strong>Kala</strong>-azar suspect:<br />
fever > 2 wks + splenomegaly or wast<strong>in</strong>g<br />
*<br />
Negative<br />
< 1/800<br />
Non kala-azar<br />
→ search other<br />
diagnosis<br />
-<br />
New case<br />
rK39 IT LEISH<br />
-<br />
Direct Agglut<strong>in</strong>ation Test (DAT)<br />
Borderl<strong>in</strong>e<br />
1/1600 – 1/12800<br />
Spleen aspirate<br />
35<br />
+<br />
Positive<br />
> 1/25600<br />
+<br />
Treatment for Primary kala-azar
Annex 8: A summary <strong>of</strong> treatment regimens for visceral leishmaniasis<br />
First l<strong>in</strong>e<br />
treatment<br />
Second<br />
l<strong>in</strong>e<br />
treatment<br />
Drug Dosage Route <strong>of</strong> adm<strong>in</strong>istration Number <strong>of</strong><br />
days<br />
1) Sodium<br />
stibogluconate<br />
(SSG )<br />
2) Meglum<strong>in</strong>e<br />
antimoniate<br />
3) Comb<strong>in</strong>ation<br />
SSG +<br />
Paromomyc<strong>in</strong><br />
Amphoteric<strong>in</strong> B<br />
deoxycholate<br />
Liposomal<br />
amphoteric<strong>in</strong> B<br />
20mg/kg per<br />
day<br />
20mg/kg per<br />
day<br />
20mg/kg per<br />
day<br />
+<br />
[11 mg base] 15<br />
mg per kg body<br />
weight per day<br />
0.75-1 mg/kg<br />
per day (daily<br />
or alternate<br />
days) for 15-20<br />
doses<br />
3-5 mg/kg per<br />
daily dose (total<br />
dose 30mg/kg)<br />
Post <strong>Kala</strong> azar dermal leishmaniasis (PKDL)<br />
1) Sodium<br />
stibogluconate<br />
(SSG )<br />
2) Meglum<strong>in</strong>e<br />
antimoniate<br />
Amphoteric<strong>in</strong> B<br />
(Fungizone,<br />
Squibb)<br />
20mg/kg per<br />
day<br />
20mg/kg per<br />
day<br />
0.75-1 mg/kg<br />
per day (daily<br />
or alternate<br />
days) for 15-20<br />
doses)<br />
36<br />
Intramuscularly/<strong>in</strong>travenously<br />
Intramuscularly/<strong>in</strong>travenously<br />
Intramuscularly/<strong>in</strong>travenously<br />
Intramuscularly<br />
30<br />
30<br />
17<br />
Infusion Number <strong>of</strong><br />
days to<br />
complete 15-<br />
20 doses<br />
Infusion 6-10 days<br />
Intramuscularly/<strong>in</strong>travenously<br />
Intramuscularly/<strong>in</strong>travenously<br />
30 - 60<br />
or up to<br />
heal<strong>in</strong>g<br />
30- 60<br />
Infusion 20 days
Annex 9: Paromomyc<strong>in</strong> Drug Insert<br />
Paromomyc<strong>in</strong> <strong>in</strong>jection<br />
Each 2 ml ampoule conta<strong>in</strong>s approximately 1 gram Paromomyc<strong>in</strong> sulphate<br />
equivalent to 750 mg Paromomyc<strong>in</strong> (375 mg/ml).<br />
Uses<br />
Paromomyc<strong>in</strong> <strong>in</strong>jection is <strong>in</strong>dicated for the treatment <strong>of</strong> Visceral Leishmaniasis<br />
(VL).<br />
Paromomyc<strong>in</strong> <strong>in</strong>jection has not been studied <strong>in</strong> patients with post-kala-azar<br />
dermal leishmaniasis (PKDL).<br />
Dosage<br />
In East Africa region only, Paromomyc<strong>in</strong> is adm<strong>in</strong>istered IM, once-a-day, for 17<br />
consecutive days <strong>in</strong> comb<strong>in</strong>ation with Sodium Stibogluconate 20mg/kg/day The<br />
recommended IM dosage for patients (5 kg <strong>and</strong> above) with normal renal<br />
function is 11 mg/kg/day paromomyc<strong>in</strong> (equivalent to approximately 15<br />
mg/kg/day paromomyc<strong>in</strong> sulfate).<br />
Daily doses <strong>in</strong> ml accord<strong>in</strong>g to body weight are shown <strong>in</strong> the table below.<br />
Body<br />
weight<br />
Daily doses<br />
(ml)<br />
Body weight Daily doses<br />
(ml)<br />
10-11kg 0.3 ml 40-42 kg 1.2 ml<br />
12-15 kg 0.4 ml 43-46 kg 1.3 ml<br />
16-18 kg 0.5 ml 47-49 kg 1.4 ml<br />
19-22 kg 0.6 ml 50-52 kg 1.5 ml<br />
23-25 kg 0.7 ml 53-56 kg 1.6 ml<br />
26-28 kg 0.8 ml 57-59 kg 1.7 ml<br />
29-32 kg 0.9 ml 60-63 kg 1.8 ml<br />
33-35 kg 1.0 ml 64-66 kg 1.9 ml<br />
36-39 kg 1.1 ml 67-69 kg 2.0 ml<br />
37
Pregnancy <strong>and</strong> breast feed<strong>in</strong>g<br />
Do not use dur<strong>in</strong>g pregnancy. Paromomyc<strong>in</strong> crosses the placenta <strong>and</strong> can cause<br />
renal <strong>and</strong> auditory damage <strong>in</strong> the unborn child. Paromomyc<strong>in</strong> is excreted <strong>in</strong><br />
breast milk <strong>and</strong> adverse effects <strong>in</strong> the breast fed <strong>in</strong>fant cannot be excluded.<br />
Contra-<strong>in</strong>dications <strong>and</strong> warn<strong>in</strong>gs<br />
Do not use <strong>in</strong> patients with hypersensitivity to paromomyc<strong>in</strong> or to other<br />
am<strong>in</strong>oglycoside antibiotics. Discont<strong>in</strong>ue use if an allergic reaction occurs.<br />
Paromomyc<strong>in</strong> is contra<strong>in</strong>dicated <strong>in</strong> patients with renal <strong>in</strong>sufficiency.<br />
In cases where paromomyc<strong>in</strong> or the comb<strong>in</strong>ation <strong>of</strong> sodium Stibogluconate <strong>and</strong><br />
paromomyc<strong>in</strong> do not lead to a VL cure at or before 6 months, do not repeat<br />
therapy. Instead, switch to another anti-leishmanial drug.<br />
.<br />
Paromomyc<strong>in</strong> as am<strong>in</strong>oglycoside has a potential for caus<strong>in</strong>g ototoxicity <strong>and</strong><br />
nephrotoxicity. Neuromuscular blockade <strong>and</strong> respiratory paralysis have been<br />
reported follow<strong>in</strong>g high doses <strong>of</strong> am<strong>in</strong>oglycosides.<br />
Concurrent use <strong>of</strong> other nephrotoxic drugs, <strong>in</strong>clud<strong>in</strong>g other am<strong>in</strong>oglycosides,<br />
vancomyc<strong>in</strong>, some <strong>of</strong> the cephalospor<strong>in</strong>s, cyclospor<strong>in</strong>, <strong>and</strong> cisplat<strong>in</strong>, or<br />
potentially ototoxic drugs such as furosemide, may <strong>in</strong>crease the risk <strong>of</strong><br />
am<strong>in</strong>oglycoside toxicity. Other factors that may <strong>in</strong>crease patient risk <strong>of</strong> toxicity<br />
are dehydration <strong>and</strong> advanced age.<br />
Side effects<br />
The most commonly reported adverse drug reactions are <strong>in</strong>jection site pa<strong>in</strong>,<br />
aspartate am<strong>in</strong>otransferase (AST) <strong>and</strong> alan<strong>in</strong>e am<strong>in</strong>otransferase (ALT)<br />
elevations, pyrexia, <strong>and</strong> an abnormal audiogram. These effects are usually mild<br />
to moderate <strong>and</strong> transient or reversible at the end <strong>of</strong> treatment. There were no<br />
age or gender differences noted <strong>in</strong> the <strong>in</strong>cidence <strong>of</strong> adverse events that occurred<br />
<strong>in</strong> patients treated with paromomyc<strong>in</strong>.<br />
In a cl<strong>in</strong>ical trial <strong>of</strong> 500 patients treated at the recommended dosage <strong>of</strong><br />
Paromomyc<strong>in</strong> monotherapy, the follow<strong>in</strong>g undesirable effects were observed:<br />
� Very common side effects ≥10% <strong>of</strong> patients: <strong>in</strong>jection site pa<strong>in</strong><br />
� Common side effects 1–10% <strong>of</strong> patients: AST <strong>and</strong> ALT elevation,<br />
pyrexia, abnormal audiogram<br />
� Uncommon side effects 0.1–1% <strong>of</strong> patients <strong>in</strong>cluded: vomit<strong>in</strong>g,<br />
38
alkal<strong>in</strong>e phosphatase elevation, blood bilirub<strong>in</strong> elevation, <strong>in</strong>jection<br />
site swell<strong>in</strong>g, ototoxicity, abscess, conductive deafness, prote<strong>in</strong>uria<br />
� Nephrotoxicity was not observed <strong>in</strong> any subjects at the<br />
recommended 11 mg/kg/day dose <strong>and</strong> duration for treat<strong>in</strong>g VL.<br />
� Ototoxicity was mild <strong>and</strong> reversible at the recommended 11<br />
mg/kg/day dose <strong>and</strong> duration for treat<strong>in</strong>g VL.<br />
� In a cl<strong>in</strong>ical trial <strong>of</strong> 381 patients treated at the recommended<br />
dosage <strong>of</strong> Paromomyc<strong>in</strong> <strong>in</strong> comb<strong>in</strong>ation with sodium<br />
stibogluconate, the follow<strong>in</strong>g undesirable effects were observed:<br />
� Very common side effects ≥10% <strong>of</strong> patients: <strong>in</strong>jection site pa<strong>in</strong>,<br />
AST elevation<br />
� Common side effects 1–10% <strong>of</strong> patients: ALT elevation,<br />
abdom<strong>in</strong>al pa<strong>in</strong>, amylase elevation, creat<strong>in</strong><strong>in</strong>e elevation, epistaxis,<br />
abnormal audiogram, alkal<strong>in</strong>e phosphatase elevation, vomit<strong>in</strong>g,<br />
thrombocythaemia, gastroenteritis<br />
� Uncommon side effects 0.1–1% <strong>of</strong> patients <strong>in</strong>cluded:<br />
thrombocytopenia, constipation, diarrhoea, dyspepsia, gastritis,<br />
nausea, toothache, <strong>in</strong>jection site swell<strong>in</strong>g, pyrexia, cellulitis,<br />
gastroenteritis, hookworm, otitis media, pharymgitis, pneumonia,<br />
ur<strong>in</strong>ary tract <strong>in</strong>fections, post kala-azar dermal leishmaniasis, blood<br />
urea <strong>in</strong>creased, Electrocardiogram changes, total prote<strong>in</strong> elevation,<br />
back pa<strong>in</strong>, headache, asthma, cough, rash,<br />
� Nephrotoxicity was observed <strong>in</strong> 0.5% <strong>of</strong> subjects at the<br />
recommended 11 mg/kg/day dose <strong>and</strong> duration for treat<strong>in</strong>g VL<br />
when comb<strong>in</strong>ed with sodium Stibogluconate.<br />
� Ototoxicity was mild <strong>and</strong> reversible. Mild changes <strong>in</strong> audiogram<br />
were seen <strong>in</strong> 1.2% patients at end <strong>of</strong> treatment <strong>and</strong> rema<strong>in</strong>ed <strong>in</strong><br />
0.4% <strong>of</strong> patients at 6 months after treatment completion at the<br />
recommended 11 mg/kg/day dose <strong>and</strong> duration for treat<strong>in</strong>g VL<br />
when comb<strong>in</strong>ed with sodium Stibogluconate.<br />
Over dosage:<br />
Symptoms: like other am<strong>in</strong>oglycosides: dizz<strong>in</strong>ess, deafness, renal failure.<br />
Treatment: Initial <strong>in</strong>tervention would be to establish an airway <strong>and</strong> ensure<br />
oxygenation <strong>and</strong> ventilation. Resuscitative measures should be <strong>in</strong>itiated<br />
promptly if respiratory paralysis occurs. If neuromuscular blockade occurs, it<br />
39
may be reversed by the IV adm<strong>in</strong>istration <strong>of</strong> calcium salts, but mechanical<br />
assistance may be necessary. Patients who have received an overdose <strong>of</strong><br />
am<strong>in</strong>oglycosides who have normal renal function should be adequately hydrated<br />
to ma<strong>in</strong>ta<strong>in</strong> an ur<strong>in</strong>e output <strong>of</strong> 3 to 5 ml/kg/hr. Patients whose renal function is<br />
abnormal may require more aggressive therapy; haemodialysis may be<br />
beneficial.<br />
Storage:<br />
Store below 30°C. Protect from light. Do not freeze.<br />
GL2.0705.5033.00 rev.02<br />
40