THE MALARIA INFECTION: A NEW THREAT?

TH 5

Introduction

Malaria is caused by infection of red blood cells with protozoan parasites of the genus Plasmodium The parasites are inoculated into the human host by a feeding female anopheline mosquito (A. donaldi, A. balabcensis, A. maculatus)

The four Plasmodium species that infect humans are P. falciparum, P. vivax, P. ovale and P. malariae

Shrinking the malaria map

40% of world population (3.3 billion people) at risk More than 650,000 deaths every year

Feachem et al. Lancet 2010

Eliminating Malaria

Malaysia unstable malaria transmission Minimal acquisition of immunity Results in people of all ages suffering acute clinical malaria High risk of progression to severe malaria if untreated Pre-elimination phase.

100,000

150,000

200,000

250,000

300,000

26,649 13,491 11,106 12,705 12,780 11,019 6,338 6,154 5,569 5,294 5,456

50,000

MALARIA CASES REPORTED IN MALAYSIA 1961-2012

0
243,870 181,495 151,822 87,432 44,226

49,526
48,007 41,708 55,068 69,127 54,831 43,545 36,853 39,890 58,958 59,208 51,921

7,390
7,010 6,650 5,306 4,725

Emergence of a new Plasmodium species - Plasmodium knowlesi

Series of severe Plasmodium malariae infection in 2004 in Sarawak ---- including 4 fatal cases PCR-confirmed as Plasmodium knowlesi Minimal knowledge about the virulence or pathogenicity in human (know-less)
Reported by a group from UNIMAS
Singh et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet 2004; 363:101724.

P. knowlesi in human is not NEW

The first case was reported in 1968 by Fong et al.

A presumptive case of naturally occurring Plasmodium knowlesi malaria in man in Malaysia. Trans R Soc Trop Med Hyg 1968; 65:83940

Back to the picture 36 years later.

Tracking back the history

Archival review- Plasmodium knowlesi DNA was detected in 35 (97.2%) of 36 blood films taken in 1996 (Malaysian Borneo) that were positive for Plasmodium malariae
(Lee K-S et al. Int J Parasitol. 2009 ; 39: 11251128.)

2000-2006: 266 (Sabah, Sarawak and Pahang) were diagnosed as P. knowlesi and only four were P. malariae cases, although 312 had been diagnosed as P. malariae by microscopy
(Cox-Singh et al., 2008)

From simian to human malaria

A malaria parasite of Old World monkeys Commonly found in long-tailed (Macaca fascicularis) and pigtailed macaques (Macaca nemestrina)

Macaca fasicularis

Macaca nemistrina

Transmission
It is transmitted mainly in forests and along forest fringes. Anophleles latens has been incriminated as the vector of P. knowlesi. --- equally attracted to monkeys and humans. Local residents and travellers to or from this region are at risk for infection.

Transmission

More cases - have no contact with monkeys or travel into the jungle. Transmission ecology is changing.

Changing Epidemiology

De-forestation and urbanisation Population migration Changes in agricultural practices

MALARIA CASES ACCORDING TO TYPE OF SPECIES 2007-2010

70%
2006 2007 2008 2009 2010

60%

57%

50%

40%

30%
25%

20%

10%

7%

8% 3%

0%

P. Falciparum

P. vivax

P. malariae

P. knowlesi

Mixed

MALARIA CASES ACCORDING TO TYPE OF SPECIES 2007-2010

70%
2006 2007 2008 2009 2010

60%

57%

50%

40%

30%
25%

20%

10%

7%

8% 3%

0%

P. Falciparum

P. vivax

P. malariae

P. knowlesi

Mixed

MALARIA CASES ACCORDING TO TYPE OF SPECIES 2011

350
300
2000 2500

250 Bil kes 200 150 100 50 0 Pv Mixed Pm Pk Pf JHR 64 6 0 7 14 KDH 22 2 1 1 34 KTN 80 1 3 108 48 MLK 11 1 0 0 3 NS 149 3 2 3 12 PHG 180 2 44 45 21 PRK 82 7 17 45 13 PRL 1 0 0 0 0 PP 29 2 1 4 50 SGOR TGU WPKL 183 5 19 29 45 7 3 4 20 16 29 4 2 1 18
Pv Mixed Pm Pk Pf 500 Bil kes 1000 0 1500

SABAH 634 102 605 71 591

SARAWAK 943 5 307 399 95

MALARIA CASES ACCORDING TO TYPE OF SPECIES 2012

MALARIA CASES ACCORDING TO TYPE OF SPECIES 2012

P.Knowlesi : 1813 kes (38%) P.Vivax : 1,461 kes (31%) P.Falciparum : 894 (19%) P.Malariae : 485 kes (10%) P.Ovale Mixed : 8 kes (0.2%) : 64 kes (1.4%)

Life cycle
The 24-h asexual life cycle - the shortest of all the known malaria (human and non-human) Daily schizont rupture leading to daily appearance of fever spikes --- loss of typical tertian or quartidian pattern. ---- also leading to rapid increase of parasite load.

Species identification

Mature parasites are indistinguishable from those of P. malariae and are commonly diagnosed as such.

mature schizont of P. malariae

mature schizont of P. knowlesi

 Ring stages resemble those of P. falciparum.

Ring stage of P. falciparum

Ring stage of P. knowlesi

Clinical features

No presenting symptoms or signs that distinguished knowlesi malaria from either falciparum or vivax malaria severe or uncomplicated. Atypical presentations vomiting, abdominal pain.

Thrombocytopenia is almost universal

Daneshvar et al. Clin Infect Dis 2009;49:852-860

Severe infection

Ranges from 6.5% to 36% Most patients developed ARDS at presentation and/or during hospitalisation Other manifestation (according to WHO criteria) are:
Hyperparasitemia Jaundice Acute renal failure

i. ii. iii.

No cases of cerebral malaria has been reported.

Cox-Singh J et al. Clin Infect Dis 2008; 46:16571

Severe knowlesi malaria at QEH, Sabah

Retrospective study from Dec 07 - Nov 09 56 patients with knowlesi malaria

22 (36%) had severe malaria, 6 (10.7%) deaths

Complications included respiratory distress (59%), acute renal failure (55%), shock (55%) Risk factors for severe disease:

Older age
William et al, Emerg Inf Dis 2011

Treatment of P knowlesi infection

A high parasite density (> 0.5% parasitaemia) with P. malariae-like parasites should be treated for P. knowlesi infection. A definitive diagnosis is made by polymerase chain reaction

Severe Disease as for treatment of P. falciparum

Intravenous artesunate 2.4mg/kg Hr 0, 12, 24 Thereafter - 2.4mg/kg daily

Treatment of uncomplicated P. knowlesi

All patients should be given combination therapy

More effective Prevents development of resistance

Recommended treatment for uncomplicated P. falciparum infection.

Artemisinin Combination Therapy

Riamet (artemether/lumefantrine) Artequine (artesunate/mefloquine)

Artemether-lumefantrine
This is currently available in Malaysia as coformulated tablets containing 20 mg of artemether and 120 mg of lumefantrine. The total recommended treatment is a 6-dose regimen of artemether-lumefantrine twice a day for 3 days.

Knowlesi malaria: points to remember

Nearly all reports of P. malariae are actually P. knowlesi P. knowlesi can be severe and potentially life-threatening Can present very similar to dengue May not appear severe on first presentation Older age group at risk of severe disease Thrombocytopenia is universal, and can be severe Resp complication is common in severe disease Treatment is the same as for P. falciparum

Knowlesi malaria - an emerging disease in South East Asia

P. knowlesi infections have also been reported from many areas in Southeast Asia: Thailand - 2004 Myanmar - 2006 The Philippines - 2008 Singapore - 2008 Sabah - 2008 Peninsular Malaysia - 2008 The increase in tourism in Southeast Asia may mean that more cases are detected in the future, including in Western countries

Summary

Plasmodium knowlesi infection has emerged as the main type of malaria in some states in this country. Successful control of malaria is hampered by the changing trend of its epidemiology. Artemisinin combination therapy is the agent of first choice for all type of malaria including knowlesi malaria. Primary care physicians should be aware of the possibility of malaria despite of lack of significant travel history.