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Malaria 2017: Update on the Clinical Literature and Management 

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DOI: 10.1007/s11908-017-0583-8 
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Malaria 2017: Update on the Clinical 
Literature and Management 
Johanna P. Daily 
Current Infectious Disease Reports 
ISSN 1523-3847 
Curr Infect Dis Rep DOI 10.1007/s11908-017-0583-8 

13 
 
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TROPICAL, TRAVEL AND EMERGING INFECTIONS (L CHEN, SECTION EDITOR) 

Malaria 2017: Update on the Clinical Literature and 

Management 
Johanna P. Daily1 
© Springer Science+Business Media, LLC 2017 
Abstract Purpose of Review Malaria is a prevalent disease in travelers to and residents of malaria-endemic regions. 
Health care workers in both endemic and non-endemic settings should be familiar with the latest evidence for the 
diagnosis, manage- ment and prevention of malaria. This article will discuss the recent malaria epidemiologic and 
medical literature to review the progress, challenges, and optimal management of malaria. Recent Findings There 
has been a marked decrease in malaria-related global morbidity and mortality secondary to malaria control programs 
over the last few decades. This ex- citing progress is tempered by continued levels of high trans- mission in some 
regions, the emergence of artemisinin- resistant Plasmodium falciparum malaria in Southeast Asia, and the lack of a 
highly protective malaria vaccine. In the United States (US), the number of travelers returning with malaria infection 
has increased over the past few decades. Thus, US health care workers need to maintain expertise in the diagnosis 
and treatment of this infection. Summary The best practices for treatment and prevention of malaria need to be 
continually updated based on emerging data. Here, we present an update on the recent literature on malaria 
epidemiology, drug resistance, severe disease, and prevention strategies. 
Keywords Malaria epidemiology . Malaria control . Malaria treatment . Drug resistance in malaria . Post-artemisinin 
delayed hemolysis 
. 
Severe malaria 
Introduction 
Plasmodium  infections  continue  to  cause  significant  morbid-  ity  and  mortality  for  residents  of  and  travelers  to 
endemic  areas.  This  protozoan  parasite  is  transmitted  through  the  bite  of  an  anopheles  mosquito  and  remains  an 
important  public  health  threat.  There  are  a  number  of  challenges  in the identi- fication and management of malaria. 
The  diagnosis  of  malaria  can  be  elusive  as  the  presenting  symptoms  are  non-specific,  and  a  delay  in diagnosis can 
result  in  poor  outcomes.  The  selection  of  an  antimalarial  regiment is dependent on the spe- cies, origin of infection, 
and  severity  of  illness.  Determination  of  appropriate  treatment  is  further  complicated  by  the  dynamic  geographic 
distribution  of  antimalarial  drug  resistance. Finally, newly reported breakthroughs in the pathogenesis and treatment 
of  severe  disease  should  inform best manage- ment practices. This review of the malaria literature highlights current 
clinical  and  public  health issues and discusses the ev- idence to guide best practices for the diagnosis, treatment, and 
prevention of malaria (Table 1). 
Global Malaria Epidemiology: Successes and Challenges 
There  has  been  a  remarkable  decrease  in  malaria  transmission  in  Africa  over  the  past  15  years,  due  to  large 
investments  in  malaria  control  programs  across  the  continent  [1,  2•].  Between  2000  and  2015,  there  has  been  an 
estimated 50% decrease in prevalence and a 40% decrease in the incidence of clinical 
Curr Infect Dis Rep _#####################_ DOI 10.1007/s11908-017-0583-8 
This article is part of the Topical Collection on Tropical, Travel and Emerging Infections 
* Johanna P. Daily 
jdaily@einstein.yu.edu 
1 Department of Medicine, Division of Infectious Diseases, Albert 
Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA 

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disease  from  Plasmodium  falciparum  infection  based  on  an  innovative  model  informed  by  field  data  (Fig.  1)  [3•]. 
This  translates  to  a  reduction  in  death  across  sub-Saharan  Africa  with  an  estimated  decrease  of  57%  (95% 
uncertainty  interval,  46  to  65)  in  the  rate  of  malaria  deaths,  from  12.5  per  10,000  population  in  2000  to  5.4  per 
10,000  population  in 2015 [4•]. The scaling up of multipronged interventions including the use of insecticide-treated 
bednets (ITNs), indoor residual spraying (IRS), seasonal malaria chemoprevention, rapid 
Table 1 Summary of important recent findings in the clinical literature and practical implications 
What’s new in clinical malaria Practical implication 
Marked global reduction in 
P. falciparum transmission 
Redouble control efforts in 
remaining high transmission areas Mass Drug Adminstration (MDA) demonstrates efficacy in low transmission areas to reduce 
infection rates 
WHO now specifies criteria for 
use of MDA 
P.falciparum artemisinin resistance is 
restricted to Southeast Asia presently 
Prolonged course of ACT to treat 
artemisinin resistant parasites 
Intravenous artesunate is a good 
alternative for severe malaria in travelers 
Monitor for post treatment 
hemolysis for 1 month 
P. vivax chloroquine resistance has been reported in geographically distinct regions worldwide 
Daily smears on treatment 
identify chloroquine resistance 
Tafenoquine may be an alternative to 
primaquine for treatment of P. vivax and P. ovale hypnozoites 
Further tafenaquine efficacy and 
safety studies underway 
Fig.  1  Reduction  in  malaria  prevalence  between  2000  and  2015  in  Africa.  Estimated prevalence of malaria infection in children 
2–10 years of age from Bhatt et al. [3•]. Maps are freely available from the Malaria 

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malaria  diagnostics,  and treatment with artemisinin combina- tion therapy have all contributed to infection reduction 
[5].  However,  some  regions  in  Africa  continue  to  have  high  trans-  mission and mortality rates, a finding associated 
with  low  use  of  preventative  and  treatment  interventions  [2•,  4•].  The  iden-  tification  of  specific  regions  with high 
malaria  disease  rates  allows  targeted  scaling  up  of  malaria  control  efforts  in  these  areas,  to  further  decrease  the 
global burden of malaria related morbidity and mortality. 
Epidemiology of Returning Travelers to the US with Malaria 
The  number  of  returning  travelers  to  the  US  with  malaria  has  been increasing over the past few decades, with 1727 
cases  reported  in 2013 [6•]. Of those who reported purpose of travel, 70% were visiting friends or relatives (VFR) in 
the  endemic  area.  The  vast  majority  of  infections  were  acquired  in Africa (82%), followed by travel to Asia (11%), 
and  the  remaining  cases  from  Central  America,  the  Caribbean,  South  America,  Oceania, and Greece. Almost every 
state  in  the  US  reported  at  least  one  case  in  2013.  Thus,  health  care  facilities  that evaluate returning travelers from 
malaria endemic areas with fever should be able to provide a rapid diagnosis and treatment of malaria. 
Children  are  likely  to be underdiagnosed with traveler’s malaria compared to adults. A retrospective review of 95 
chil-  dren  and  adults  hospitalized  for  traveler’s  malaria  between  2005 and 2012 was carried out in the Bronx [7]. P. 
falciparum infection was responsible for 86% of infections, 
Atlas Project (http://www.map.ox.ac.uk/) under the Creative Commons Attribution 3.0 Unsupported License 
 
83%  of  patients  were  VFR  and  18%  had severe malaria. Children were more likely to have been seen previously by 
a  health  care  worker  and  not  diagnosed  with  malaria  compared  to  adults  (43  vs  13%,  p  =  0.002).  The  under 
diagnosis  of  malaria  in  children  may  be  due  to  their  significantly  higher  rate  of  gastrointestinal  symptoms  as 
compared  to  adults,  which  mimic  common  pediatric  illnesses  such  as  viral  gastro-  enteritis. As malaria can present 
with  diverse  and  non-specific  symptoms,  a  diagnostic  test  should  be  a  priority  in  all  febrile travelers with a history 
of visiting a malaria-endemic area. 
Microscopy  provides  speciation  and  parasite  quantification  and  the  CDC  provides  educational  material  for 
diagnostic  procedures  for  malaria,  including  a  telediagnostic  service [8]. However, adequate microscope equipment 
and  expertise  may  not  be  readily  available.  Rapid  diagnostic  tests  are  excel-  lent  alternatives  and  in  many  settings 
outperform  microscopy  for  the  diagnosis  of  malaria. These tests are less reliable for non-falciparum malaria and are 
less  sensitive  than  microsco-  py;  however,  they  have  provided  a  key  diagnostic  resource  for  both  malaria  control 
programs  worldwide  and  for  US  health  care  facilities.  Updated  information  on  the  use  and  evaluation  of  rapid 
diagnostic tests is available at http://www2.wpro. who.int/sites/rdt/home.htm. 
Diagnosis and Treatment of Severe Malaria 
Clinical  and  laboratory  criteria  are  used  to  establish  the  diag-  nosis  of  severe  malaria,  which  requires  aggressive 
treatment,  particularly  for  travelers  who  often  have no immunity [9•]. There were 270 travelers in the US diagnosed 
with  severe  malaria  in  2013,  with  233  (86%)  cases  due  to  P.  falciparum  [6•].  The  severe  disease  criteria  for  these 
travelers  included  renal  failure,  severe  anemia,  and/or  cerebral  malaria.  Severe  cerebral  edema  and  brainstem 
herniation was reported in some of the malarial deaths in this case series. The striking phenom- ena of brain swelling 
was  recently  described  in  detail  in  a large cohort of Malawian children with cerebral malaria (CM) where high rates 
of  brain  swelling  had  the  greatest  association  with  death  (adjusted  OR  7.5  (95%  2.1–26.9))  and  associated  with 
brainstem  herniation  [6•,  10].  High  rates  of  brain  swell-  ing  are  associated  with  elevated  levels  of  inflammatory 
cyto-  kines  and  lipid  metabolites  of  the  phospholipase  A2  pathway,  although  the  mechanisms  of  this  complication 
are  not  under-  stood  [11].  The  optimal  adjunctive  therapy  to  treat  CM-related  brain  swelling  remains  to  be 
determined. 
The  majority  of  travelers  with  severe  malaria  in  the  US  in 2013 were treated appropriately with quinidine (55%) 
and  intravenous  artesunate  (16%),  as  both  drugs  are  recommended  for  treatment  of  severe  malaria  [6•].  Although 
parenteral  ther-  apy  is  the  standard  of care for severe malaria, 30% of patients were treated with an oral antimalarial 
regimen [6•]. Furthermore, some of the severe malaria deaths were 

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associated  with  a  delay  in  diagnosis.  Best  practice  manage-  ment  of  severe  malaria  requires  a  rapid  diagnosis, 
intravenous antimalarial therapy, and supportive care as needed. 
Quinidine  (a  stereoisomer  of  quinine)  is  the  only  FDA-  approved  treatment  for  severe  malaria  in  the  US; 
however,  its  availability  is  decreasing  as  newer  generation  antiarrhyth-  mic  drugs  are  being  used.  The  CDC  can 
provide  artesunate  as  an  alternative  treatment  for  severe  malaria,  if  the  patient  ful-  fills  eligibility  criteria  [12]. 
Excellent  outcomes  with  the  use  of  intravenous  artesunate  for  severe  or  complicated  malaria  was recently reported 
through  a  retrospective  case  series  of  102  patients  treated  in the US which included a 7-day follow-up period. They 
found  that  artesunate  was  indeed  commonly  re-  quested  due to lack of quinidine availability and that artesunate is a 
safe  and  clinically  beneficial  alternative  to  quin-  idine  [13].  However,  it  is  important  to  recognize  that  a  late 
hemolytic  complication  can  occur  after  the  use  of  intravenous  artesunate.  Post-artemisinin  delayed  hemolysis 
(PADH)  oc-  curs  at  least  7  days  after  the  first  dose  of  intravenous  artesunate  and  is  defined  as a decrease of ≥10% 
hemoglobin  in  the  setting  of  a  haptoglobin <0.1 g/L and an increase in lactate dehydro- genase (LDH) of >390 U/L. 
Some  patients  with  PADH  require  blood  transfusions  and  experts  suggest  that  patients  who  re-  ceive  intravenous 
artesunate for severe malaria should be test- ed for hemolysis weekly for 4 weeks after treatment [14, 15]. 
Changing Patterns of Antimalarial Resistance 
Artemisinins  remain  the  mainstay  of  therapy  and  are  used  in  combination  with  a  second  agent  to  forestall  drug 
resistance  [9•].  Artemisinins  are  superior  to  quinine  for  severe  disease  to  prevent  death:  are available in parenteral, 
oral,  and  rectal  for-  mulations;  and  have  the  additional  benefit  of  clearing  game-  tocytes,  the  transmissible form of 
malaria  [9•].  One  potential  threat  to  the  large  reduction  in  malaria  prevalence  is  the  emer-  gence  of  artemisinin 
resistance  in  Southeast  Asia.  P.  falciparum  resistance  to  artemisinin  was  first  reported  in  Southeast  Asia  a  decade 
ago  and  now  has  become  prevalent  in  regions  of  Cambodia,  Vietnam,  Laos,  Thailand,  Myanmar,  and  China [16•]. 
To  date,  it  does  not  appear  that artemisinin resistance has spread outside these regions, based on a recent worldwide 
survey  of  artemisinin  genotypic  resistance  [16•].  In  order  to  treat  patients  in  regions  with  artemisinin-resistant  iso- 
lates,  the  duration  of  antimalarial  therapy  should be extended from 3 to 6 days, which has been associated with cure 
rates  up  to  97.7%  (95%  confidence  interval,  90.9  to  99.4)  at  42  days  in  regions  that  had  high  failure rates with the 
3-day  course  [17].  Future  studies  will  need  to  determine  the  durability  of  this  strategy.  Strategies  to  contain 
artemisinin  resistance  include adding a dose of primaquine to the treatment course, which is more effective at killing 
gametocytes, to further reduce the 
 
prevalence of these drug-resistant transmissible forms within a population [9•]. 
Plasmodium vivax 
P.  vivax  is  the  most  prevalent  human  malaria,  has a prolonged liver phase (hypnozoite), and can occasionally cause 
severe  disease  [18•].  P.  vivax  is  generally  sensitive  to  chloroquine; however, reports of chloroquine resistance have 
been  emerg-  ing  and  resistance  is  well  established  in  Indonesia  and  Oceania.  A  meta-analysis  to  determine  the 
global  extent  of  chloroquine  resistance evaluated 129 clinical trials and 26 case reports [19•]. Studies of drug failure 
in  P.  vivax  are  com-  plicated  by  the  hypnozoite-induced  relapse  (which  relapse  typically  after  1  month  or  longer 
after  the  primary  infection),  which  could  be  misclassified  as  a  drug  resistant  parasite.  Thus,  in  this  meta-analysis, 
they  reported  recurrences  occurring  within  1  month  of  a  treated  infection;  in  addition,  they highlighted studies that 
documented  recurrences  occurring  in  the  presence  of  adequate  blood  concentrations  of  chloroquine,  in  order  to 
provide  robust  evidence  of drug resistance. Chloroquine resistance was present in 58 study sites (53%). Microscopic 
clearance  of  parasitemia  by  day  3  of  treatment  was found to be a highly predictive marker of P. vivax chlo- roquine 
sensitivity.  Currently,  the  WHO  recommends  either  artemisinin  combination  therapy  or  chloroquine  as  first-line 
treatment  for  Plasmodium  vivax,  Plasmodium  ovale,  Plasmodium  malariae,  or  Plasmodium  knowlesi  [9•].  A  rea- 
sonable  strategy  for  treatment  of  travelers  with  P.  vivax  is  to  treat  with  chloroquine  and follow daily smears. If the 
patient  is  from  a  known  chloroquine-resistant  area,  then  treatment  with  artemisinin  combination  therapy  is 
appropriate.  In  both  cases,  treatment  should  be  followed  with  a  course  of  primaquine  if  they  have  a  normal 
glucose-6-phosphate dehydrogenase (G6PD) level to treat the hypnozoite phase and prevent relapse. 
The  hypnozoite  stages  of  P.  vivax  serves  as  a  silent  reser-  voir,  to  perpetuate  transmission  within  a  population. 
Primaquine  clears the liver stage; however, the limitations of primaquine are the need for a 14 day course, the risk of 
he-  molysis  in  patients  with  G6PD  deficiency,  and  reports  of drug failure at 15 mg/day dose regimen [20]. A single 
dose  of  tafenoquine  has  been  tested  as  an  alternative  liver-stage  anti-  malarial  and  there  is evidence that this single 
dose may be more effective than 14 days of primaquine to prevent relapses at 6 months of follow-up (RR 0.29, (95% 
CI  0.10–0.84)  [21].  The  availability  of  a  safe  and  single-dose  therapy  to  clear  hypnozoites  could  have  a  major 
impact  on  individual  care  and  P.  vivax  control  and  eradication  programs.  Additional,  large  sample  size data on the 
risk  of  tafenoquine-induced  he-  molysis  in  patients  with  G6PD  deficiency  and  safety/efficacy  in  children  and 
pregnant women are needed. 

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Plasmodium knowlesi 
P.  knowlesi  is  a  zoonotic  malaria  that  is  notable  for  a  24-h  life  cycle,  its  association  with  severe  disease,  and 
challenges  in  diagnosis.  A  large  focus  of  P.  knowlesi  malaria  was  identified  in  Malaysia  over  a decade ago, and P. 
knowlesi  has  since  become  their  most  prevalent  malaria  with  ongoing  transmis-  sion  in  additional Southeast Asian 
countries  [22,  23•].  P.  knowlesi  can  be  misdiagnosed  as  the  typically  benign  P.  malarie  due  to  the  histological 
similarities  of  the  trophozo-  ite  and  schizont  stages  by  microscopy.  Rapid  diagnostic  tests  have  only  limited 
sensitivity  and  specificity  for  P.  knowlesi.  This  species  can  result  in  severe  disease,  partially  due  to  its  association 
with  hyperparasitemia.  Of  note,  the  severe  disease  criteria  of  hyperparasitemia  for  this  species  is  >100,000/uL, 
which is lower than that of P. falciparum [9•]. 
P.  knowlesi  is  the  only  major zoonotic Plasmodium infec- tion of humans, where macaques serve as the reservoir 
and  transmit  infection  to  humans  via  infected  mosquitoes;  infec-  tions transmitted between human hosts through an 
anopheles  mosquito  do  not  occur.  The  existence  of  an  animal  reservoir  may  make  elimination of P. knowlesi more 
challenging  [24].  The  optimal  treatment strategies are being tested in clinical trials. Both artesunate–mefloquine and 
chloroquine  were  found  to  be  highly  efficacious  for  the  treatment  of  P.  knowlesi  in  Malaysia  in  an  open-label 
randomized  con-  trolled  trial.  However  artensuate–mefloquine  resulted  in  a  more  rapid  parasite  clearance  and 
shorter time to fever reso- lution [25]. 
Preventative Measures 
Mass  Drug  Administration  One  approach  to  reduce  trans-  mission  that  is  being  revisited  by  malaria  control 
practitioners  is  the implementation of Mass Drug Administration (MDA). MDA is the distribution of a curative dose 
of  an  antimalarial  drug  to  an  entire  population  without  first  testing  for  infection.  MDA  has  had mixed successes in 
the  past  and  its  role  as  part  of  a  malaria  control  campaign  has  been  debated.  Recently,  the  WHO  Malaria  Policy 
Advisory  Committee  updated  their  rec-  ommendations  to  consider  the  use  of  MDA  in  the  settings  of  low 
transmission  approaching  elimination,  in  regions  with  multi-drug  resistance  as  a  component  of  malaria elimination 
and  as  part  of  an  immediate  response  to  malaria  epidemics  [26,  27].  A  cluster-randomized  controlled  trial  in 
Southern  Province,  Zambia,  was  used  to  assess  the  short-term  impact  of  two  rounds  of  dihydroartemisinin  plus 
piperaquine  MDA  compared  with  no  MDA.  They  found  an  87%  relative  reduc-  tion  in  infection  prevalence 
(adjusted  OR,  0.13;  95%  CI,  0.02–0.92;  p  =  0.04)  after  accounting  for  confounding  factors  [28].  Importantly,  the 
reduction in infection prevalence only occurred in the lower transmission setting, with no effect in 
 
the  high  transmission  region.  More  studies  are  underway  in  to  further  identify  the  role  and  efficacy  of  MDA  in  a 
malaria control programs. 
Chemoprophylaxis  P.  falciparum  infection  during  pregnancy  can  result  in  infection  of  the  placenta  to  compromise 
its  normal  functions  and  therefore  result  in  premature  delivery  and  fetal  loss.  Intermittent  preventative  therapy, 
starting  in  the  second  trimester  with  sulfadoxine–primethamine  (SP)  has  been  used  to  prevent  maternal  malaria; 
however,  its  efficacy  has  dimin-  ished  due  to  the  development  of  SP  resistance  [9•].  Artemisinin  combination 
therapies  have  been  studied  as  an  al-  ternative  prophylactic strategy. In one region of Kenya with high transmission 
and  SP  resistance,  a  study  showed  that  intermittent preventive treatment with dihydroartemisinin–piperaquine com- 
pared  to  SP  was  associated  with  a  lower  incidence  of  malaria  infection  during  pregnancy (192·0 vs 54·4 events per 
100  person-years;  incidence  rate  ratio  [IRR]  0·28,  95%  CI  0·22–0·  36;  p  <  0·0001)  [29].  Ultimately,  the  best 
antimalarial  regiments  and  strategies  to  prevent  malaria  during  pregnancy  will  depend  on  local  SP  resistance  rates 
and transmission intensity. 
Seasonal  malaria  prophylaxis  with  SP  plus  amodiaquine  to  children  under  5  years  of  age  in  moderate  to  high 
transmission  areas  of  Africa  reduces  infection  and  is  recommended  by  the  WHO  [9•].  In  some  regions,  older 
children  bear  a  large  burden  of  disease  from  malaria  and  potentially  could  also  benefit  from  seasonal  malaria 
prophylaxis.  A  large  study  of  chemopreven-  tion  in  children  under  the  age  of  10  years  in  Senegal,  found  that 
SP-amodiaquine  significantly  reduced  the  incidence of malaria and severe malaria, and that this protection extended 
to  subjects  greater  than  5  years  of  age  [30].  These  data  suggest  that seasonal chemoprophylaxis could contribute to 
reducing disease in older children. 
Vaccine  An  effective  vaccine  against  malaria  has  been  a  long  sought  goal.  A  vaccine  that  targets  the  sporozoite 
stage  of  P.  falciparum  (RTS,S/AS01)  has  demonstrated  protection  in  children  in  Africa.  The  RTS,S/ASO1 vaccine 
(4  doses)  was  associated  with  rates  of  protection  against  clinical  malaria  of  36.3%  (95%  confidence  interval  [CI], 
31.8  to  40.5)  among  children  5 to 17 months of age and 25.9% (95% CI, 19.9 to 31.5) among young infants (6 to 12 
weeks)  (n  =  15,459)  [31].  This  protection  wains  over  time and in a 7-year follow-up subanalysis of 5–17 months of 
age  subjects  receiving  three  doses,  children  in  regions  of  high  transmission had higher- than-average infection with 
malaria  parasites  [32].  This  ma-  laria  rebound  may  occur  because  protection  against the spo- rozoite stage prevents 
blood-stage  infections  and  thus  vaccine  recipients  have  less  immunity  to  blood-stage  parasite  antigens.  The  WHO 
recently  announced  a  study  of  the  vaccine’s  pro-  tective efficacy in the context of routine use in children aged 5–17 
months old, using the four-dose regiment in Ghana, Kenya, and Malawi [33, 34]. Additional malaria vaccine 

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candidates  that  target  additional  stages  of  the  life  cycle  are  in  clinical  development  [35•].  Continued  investments 
from pub- lic sources and philanthropy will be critical to advance the vaccine agenda forward. 
Resources 
The  WHO  Guidelines  for  the  treatment  of  malaria—third  edi-  tion  is  an  excellent  and  comprehensive  resource  on 
malaria  [9•].  This  updated  document  provides  detailed  background  on  a  range  of  clinical  topics  and  their 
recommendations  are accom- panied by a quality of evidence rating. Some of the updated guidelines in 2015 include 
the  recommendation  of  IVartesunate  for  a  pregnant  woman  with  severe  disease  in  all  stages  of  preg-  nancy,  the 
first-line  use  of  artemisinin  combination  therapy  (or  chloroquine)  for  non-falciparum  malarias  and  the  use  of 
primaquine  during  treatment  of  active  infections  with  artemisinin  combination  therapies  to  reduce  transmissible 
forms  in  patients  with  P.  falciparum  infection  in  low-  transmission  regions.  The  CDC  also  provides  a  critical  and 
outstanding  resource  to  US  health  care  workers  for  the  preven-  tion  and  management  of  travelers  malaria  [36•]. 
Their  24-h  hotline  provides  expert  guidance  on  diagnosis  and  treatment  of  malaria  and  the  CDC  can  provide 
intravenous  artesunate  as  indicated.  They  can  be  reached  via  the  CDC  Malaria  Hotline  (770–488-7788)  from  9:00 
a.m.  to  5:00  p.m.  Eastern  Time.  For  emergency  consultation  after  hours,  call  770–488-7100  and  request  to  speak 
with a CDC Malaria Branch Clinician. 
Conclusions 
There  have  been  tremendous  strides  in  controlling  and  de-  creasing  malaria  infections  worldwide.  Experts  in 
diagnostics,  drug  development,  disease  modeling,  clinical  research,  vac-  cine  development  and  others  have  moved 
the  field  forward  due  to  investments  by  committed  donors.  The march toward further reduction in transmission and 
possible  elimination  will require continued efforts and resources. For now, malaria re- mains an important infectious 
disease  in  endemic  regions  and  for  travelers,  and  best  practices  for malaria control and man- agement will continue 
to evolve. 
Acknowledgments The author acknowledges Dr. Lin Hwei Chen and Dr. Margaret Aldrich for their critical reviews of the 
manuscript. 
Compliance with Ethical Standards 
Conflict of Interest Dr. Daily declares no conflicts of interest. 
Human  and  Animal  Rights  and  Informed  Consent All reported studies/experiments with human or animal subjects performed by 
the authors have been previously published and complied with all applicable 
 
ethical standards (including institutional/national research committee standards). 

References 
Papers of particular interest, published recently, have been highlighted as: 
• Of importance 
1. World Health Organization. World Malaria Report 2014. Geneva. 2.• Noor AM, Kinyoki DK, Mundia CW, Kabaria CW, 
Mutua JW, Alegana VA, et al. The changing risk of Plasmodium falciparum malaria infection in Africa: 2000–10: a spatial and 
temporal analy- sis of transmission intensity. Lancet. 2014;383(9930):1739–47. doi:10.1016/S0140-6736(13)62566-0. Striking 
graphical representations of changes in malaria prevalence between 1980–2012 using 26,746 space–time survey data points of 
3,575,418 person-observations across Africa. 3.• Bhatt S, Weiss DJ, Cameron E, Bisanzio D, Mappin B, Dalrymple U, et al. The 
effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature. 2015;526(7572):207–11. 
doi:10.1038/nature15535. Innovative analysis of a large database of malaria field surveys. Their maps and additional updated 
maps are available from the Malaria Atlas Project (http://www.map.ox.ac.uk/). 4.• Gething PW, Casey DC, Weiss DJ, Bisanzio 
D, Bhatt S, Cameron E, et al. Mapping Plasmodium falciparum Mortality in Africa be- tween 1990 and 2015. N Engl J Med. 
2016;375(25):2435–45. doi: 10.1056/NEJMoa1606701. A landmark modeling study demonstrating reduction in malaria mortality 
in Africa over fifteen years. Detailed mapping to 5-km2 spatiotemporal esti- mates identify hotspots of mortality linked to low 
coverage of antimalarial treatment. 5. Hemingway J, Shretta R, Wells TN, Bell D, Djimde AA, Achee N, et al. Tools and 
strategies for malaria control and elimination: what do we need to achieve a grand convergence in malaria? PLoS Biol. 
2016;14(3):e1002380. doi:10.1371/journal.pbio.1002380. 6.• Cullen KA, Mace KE, Arguin PM, Centers for Disease C, 
Prevention. Malaria Surveillance—United States, 2013. MMWR Surveill Summ. 2016;65(2):1–22. 
doi:10.15585/mmwr.ss6502a1. Summarizes traveler’s malaria cases to the US in 2013. Provides detailed epidemiological data. 
The severe disease case vignettes are highly instructive. 7. Goldman-Yassen AE, Mony VK, Arguin PM, Daily JP. Higher rates 
of misdiagnosis in pediatric patients versus adults hospitalized with imported malaria. Pediatr Emerg Care. 2016;32(4):227–31. 
doi:10.1097/PEC.0000000000000251. 8. Mathison BA, Pritt BS. Update on malaria diagnostics and test 
utilization. J Clin Microbiol. 2017; doi:10.1128/JCM.02562-16. 9.• Guidelines for the treatment of malaria-3rd edition. 
Geneva, Switzerland; 2015. Excellent updated resource with detailed background information and graded management 
recommendations. 10. Seydel KB, Kampondeni SD, Valim C, Potchen MJ, Milner DA, Muwalo FW, et al. Brain swelling and 
death in children with cere- bral malaria. N Engl J Med. 2015;372(12):1126–37. doi:10.1056/ NEJMoa1400116. 11. Pappa V, 
Seydel K, Gupta S, Feintuch CM, Potchen MJ, Kampondeni S, et al. Lipid metabolites of the phospholipase A2 pathway and 
inflammatory cytokines are associated with brain vol- ume in paediatric cerebral malaria. Malar J. 2015;14:513. doi:10. 
1186/s12936-015-1036-1. 

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12. Artesunate is available to treat severe malaria in the United States. Centers for Disease Control and Prevention. 2017. 
https://www.cdc. gov/malaria/diagnosis_treatment/artesunate.html. Accessed 27 March 2017. 13. Twomey PS, Smith BL, 
McDermott C, Novitt-Moreno A, McCarthy W, Kachur SP, et al. Intravenous artesunate for the treat- ment of severe and 
complicated malaria in the United States: clin- ical use under an investigational new drug protocol. Ann Intern Med. 
2015;163(7):498–506. doi:10.7326/M15-0910. 14. Charles M, Patterson JM, Asadi L, Houston S. Delayed hemolysis after 
parenteral artesunate therapy for severe malaria in two returning Canadian travelers. Am J Trop Med Hyg. 2015;93(4): 819–21. 
doi:10.4269/ajtmh.15-0268. 15. Rolling T, Agbenyega T, Krishna S, Kremsner PG, Cramer JP. Delayed haemolysis after 
artesunate treatment of severe malaria— review of the literature and perspective. Travel Med Infect Dis. 2015;13(2):143–9. 
doi:10.1016/j.tmaid.2015.03.003. 16.• Menard D, Khim N, Beghain J, Adegnika AA, Shafiul-Alam M, Amodu O, et al. A 
Worldwide Map of Plasmodium falciparum K13-Propeller Polymorphisms. N Engl J Med. 2016;374(25): 2453–64. 
doi:10.1056/NEJMoa1513137. An analysis of 14,037 malaria samples across the globe to assess the distribution of artemisinin 
genotypic resistance. They provide detailed standardized methods to detect genotypic resistance and a molecular method to test if 
parasite K13 mutations confer in vitro artemisinin resistance. 17. Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, 
Suon S, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371(5):411–23. 
doi:10.1056/ NEJMoa1314981. 18.• Howes RE, Battle KE, Mendis KN, Smith DL, Cibulskis RE, Baird JK, et al. Global 
Epidemiology of Plasmodium vivax. Am J Trop Med Hyg. 2016;95(6 Suppl):15–34. doi:10.4269/ajtmh.16-0141. Excellent 
review of P. vivax epidemiology, chloroquine resistance, severe disease, and biology. 19.• Price RN, von Seidlein L, Valecha N, 
Nosten F, Baird JK, White NJ. Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis. 
Lancet Infect Dis. 2014;14(10):982–91. doi:10.1016/S1473-3099(14)70855-2. The largest meta-analysis of studies reporting on 
chloroquine resis- tance in P. vivax endemic regions from 1960–2014. The challenges of defining chloroquine resistance in P. 
vivax are well described. 20. Ebstie YA, Abay SM, Tadesse WT, Ejigu DA. Tafenoquine and its potential in the treatment and 
relapse prevention of Plasmodium vivax malaria: the evidence to date. Drug design, development and therapy. 2016;10:2387–99. 
doi:10.2147/DDDT.S61443. 21. Rajapakse S, Rodrigo C, Fernando SD. Tafenoquine for preventing relapse in people with 
Plasmodium vivax malaria. Cochrane Database Syst Rev. 2015;(4):CD010458. doi:10.1002/14651858. CD010458.pub2. 22. 
Singh B, Daneshvar C. Human infections and detection of Plasmodium knowlesi. Clin Microbiol Rev. 2013;26(2):165–84. 
doi:10.1128/CMR.00079-12. 23.• Barber BE, Grigg MJ, William T, Yeo TW, Anstey NM. The Treatment of Plasmodium 
knowlesi Malaria. Trends in parasitolo- gy. 2017;33(3):242–53. doi:10.1016/j.pt.2016.09.002. Excellent review of P. knowlesi 
antimalarial treatment studies, and recommendations for optimal management of infection in adults, children, during pregnancy 
and for severe disease. 24. Shearer FM, Huang Z, Weiss DJ, Wiebe A, Gibson HS, Battle KE, et al. Estimating geographical 
variation in the risk of zoonotic Plasmodium knowlesi infection in countries eliminating malaria. PLoS Negl Trop Dis. 
2016;10(8):e0004915. doi:10.1371/journal. pntd.0004915. 
 
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Curr Infect Dis Rep _#####################_ Page 7 of 7 _####_ 
View View publication publication stats stats 25. Grigg MJ, William T, Menon J, Dhanaraj P, Barber BE, Wilkes CS, 
under ten years of age in Senegal: a stepped-wedge 
cluster- et al. Artesunate-mefloquine versus chloroquine for treatment of 
randomised trial. PLoS Med. 2016;13(11):e1002175. 
doi:10.1371/ uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT 
journal.pmed.1002175. KNOW): an open-label, 
randomised controlled trial. Lancet Infect 
31. RTS, S Clinical Trials Partnership. Efficacy and safety of 
RTS,S/ Dis. 2016;16(2):180–8. doi:10.1016/S1473-3099(15)00415-6. 
AS01 malaria vaccine with or without a booster dose 
in infants and 26. Newby G, Hwang J, Koita K, Chen I, Greenwood B, von Seidlein 
children in Africa: final results of a phase 3, individually 
L, et al. Review of mass drug administration for malaria and its 
randomised, controlled trial. Lancet. 
2015;386(9988):31–45. doi: operational challenges. Am J Trop Med Hyg. 2015;93(1):125–34. 
10.1016/S0140-6736(15)60721-8. 
doi:10.4269/ajtmh.14-0254. 
32. Olotu A, Fegan G, Wambua J, Nyangweso G, Leach 
A, Lievens M, 27. WHO Evidence Review Group meeting report. Mass drug admin- 
et al. Seven-Year Efficacy of RTS,S/AS01 Malaria 
Vaccine among istration, mass screening and treatment and focal screening and 
Young African Children. N Engl J Med. 
2016;374(26):2519–29. treatment for malaria. Geneva, April 20–22, 2015. Report No.: 
doi:10.1056/NEJMoa1515257. 
WHO/HTM/GMP/MPAC/2015.9. 
33. Ghana, Kenya and Malawi to take part in WHO 
malaria vaccine 28. Eisele TP, Bennett A, Silumbe K, Finn TP, Chalwe V, Kamuliwo M, 
pilot programme. Geneva: World Health Organization; 
2017. et al. Short-term impact of mass drug administration with 
34. World Health Organization. Malaria vaccine: WHO position 
paper, dihydroartemisinin plus piperaquine on malaria in Southern 
January 2016 - Recommendations. Vaccine. 2017. 
doi:10.1016/j. Province Zambia: a cluster-randomized controlled trial. J Infect 
vaccine.2016.10.047. Dis. 2016;214(12):1831–9. 
doi:10.1093/infdis/jiw416. 
35.• Birkett AJ. Status of vaccine research and 
development of vaccines 29. Desai M, Gutman J, L'Lanziva A, Otieno K, Juma E, Kariuki S, 
for malaria. Vaccine. 2016;34(26):2915–20. 
doi:10.1016/j.Vaccine. et al. Intermittent screening and treatment or intermittent preventive 
2015.12.074. Updated status report of the current vaccine 
treatment with dihydroartemisinin-piperaquine versus intermittent 
pipeline, organized by lifecycle stage target. Data adapted 
preventive treatment with sulfadoxine-pyrimethamine for the con- 
from WHO table of global malaria vaccine projects. trol of 
malaria during pregnancy in western Kenya: an open-label, 
36.• CDC. Malaria. Centers for Disease Control and Prevention, 
three-group, randomised controlled superiority trial. Lancet. 
Atlanta, GA. https://www.cdc.gov/malaria/. Accessed 14 
2015;386(10012):2507–19. doi:10.1016/S0140-6736(15)00310-4. 
Apr 2017. Excellent resource for background, 
diagnosis and 30. Cisse B, Ba EH, Sokhna C, NDiaye JL, Gomis JF, Dial Y, et al. 
management information. Consultation regarding 
Effectiveness of seasonal malaria chemoprevention in children 
management readily available.