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The Journal of Infectious Diseases
CORRESPONDENCE
Infectivity of Microscopic and
Submicroscopic Malaria Parasite
Infections in Areas of Low
Malaria Endemicity
TO THE EDITOR—The contribution of lowdensity, subpatent Plasmodium falciparum infection to mosquito infection
and onward transmission of malaria has
received much recent attention as a determinant of the success of malaria elimination strategies. The study by Lin et al [1]
addresses this issue in the context of low
malaria transmission intensity in Cambodia. The authors observed that 5.9% of
adults with symptomatic malaria were infectious in mosquito feeding experiments
and that the vast majority of these infections (96%) arose from patients whose
blood had microscopically detectable gametocytes. The study provides valuable
information on infectivity in this particular group (ie, adults with clinical malaria
who have presented to the hospital). It
also suggests that infectivity in areas
where individuals seek medical care early
in their infection, with fewer mature gametocytes, would be lower than in areas
where clinic attendance is delayed, perhaps because symptoms take longer
to develop and/or individuals postpone
seeking treatment, and gametocyte levels
have more time to increase.
Although these observations made in
the Cambodian study are valuable, there
are several important considerations when
using these clinic-based observations to
draw broader conclusions on the human
infectious reservoir for malaria. In many
settings, the majority of malaria parasite infections do not elicit effective care-seeking
behavior but persist as asymptomatic infections. A recent large epidemiological
study in Cambodia, Vietnam, and along
the Thailand-Myanmar border showed
that 20% of the population in these
settings harbored falciparum or vivax infections, most of which were afebrile [2].
Imwong et al [3] recently demonstrated
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that the mean density of these asymptomatic infections is approximately 5
parasites/μL; the majority of infections
are thereby present at densities that are
unlikely to be detected by microscopy or
rapid diagnostic tests [4, 5]. It is the contribution of these asymptomatic and often
submicroscopic infections to the infectious
reservoir that is poorly characterized.
The conclusion of Lin et al that ultrasensitive diagnostic assays are not required to identify individuals who are
most infectious to mosquitoes is most
probably correct. It is, however, still very
much an open question what proportion
of all mosquito infections is caused by individuals with clinical malaria who are
seeking treatment and what proportion
is caused by individuals with asymptomatic, chronic infections that may be submicroscopic. Indeed, in an earlier study
in Thailand, Pethleart et al [6] concluded
that the infectious reservoir was largely
driven by the latter group (ie, infected
individuals who did not present to
clinics). That study also concluded that
submicroscopic gametocytes were an
important source of mosquito infections
in this population. Moreover, the true relevance of the results from any of the artificial mosquito infections needs to be
balanced by natural mosquito dynamics
such as local abundance, biting rates,
and species-specific susceptibility to infection [7].
Ultimately, where the health system is
able to (or can be improved to be able
to) rapidly identify and treat infections,
it seems reasonable to assume that the
duration of symptomatic infections will
be shortened, resulting in fewer infectious
individuals. This could have an important
impact on overall malaria transmission, as
suggested in the optimistic conclusions by
Lin et al. However, in many settings in Africa and Asia, asymptomatically infected
individuals vastly outnumber those with
CORRESPONDENCE
symptoms, and the lack of interaction
with health systems means that many infections remain untreated. It is imperative
that the identification and treatment of
malaria by health facilities remain the cornerstone of malaria control programs, but
specific targeting of asymptomatic infections is likely to accelerate the progress toward elimination. Further studies on the
importance of asymptomatic and submicroscopic malaria parasite infections for
onward transmission will facilitate this
progress.
Notes
Financial support. This work was supported
by the Bill and Melinda Gates Foundation (grant
AFIRM OPP1034789) and the European Research
Council (fellowship ERC-2014-StG 639776 to
T. B.).
Potential conflicts of interest. All authors:
No reported conflicts. All authors have submitted
the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors
consider relevant to the content of the manuscript have been disclosed.
Bronner P. Gonçalves,1 Chris Drakeley,1 and
Teun Bousema2
1
Department of Immunology and Infection, London School of
Hygiene and Tropical Medicine, United Kingdom; and
2
Department of Medical Microbiology, Radboud University
Medical Center, Nijmegen, The Netherlands
References
1. Lin JT, Ubalee R, Lon C, et al. Microscopic Plasmodium falciparum gametocytemia and infectivity
to mosquitoes in Cambodia. J Infect Dis 2016;
213:1491–4.
2. Imwong M, Nguyen TN, Tripura R, et al. The epidemiology of subclinical malaria infections in SouthEast Asia: findings from cross-sectional surveys in
Thailand-Myanmar border areas, Cambodia, and
Vietnam. Malar J 2016; 213:1322–9.
3. Imwong M, Stepniewska K, Tripura R, et al.
Numerical distributions of parasite densities during
asymptomatic malaria. J Infect Dis 2016; 213:
1322–9.
4. Slater HC, Ross A, Ouedraogo AL, et al. Assessing the
impact of next-generation rapid diagnostic tests on
Plasmodium falciparum malaria elimination strategies. Nature 2015; 528:S94–101.
5. Wu L, van den Hoogen LL, Slater H, et al. Comparison of diagnostics for the detection of asymptomatic Plasmodium falciparum infections to
inform control and elimination strategies. Nature
2015; 528:S86–93.
6. Pethleart A, Prajakwong S, Suwonkerd W, Corthong
BWebber R, Curtis C. Infectious reservoir of
Plasmodium infection in Mae Hong Son Province,
north-west Thailand. Malar J 2004; 3:34.
7. Stone W, Goncalves BP, Bousema T, Drakeley C.
Assessing the infectious reservoir of falciparum malaria:
past and future. Trends Parasitol 2015; 31:287–96.
Received 14 January 2016; accepted 25 January 2016; published online 9 February 2016.
Correspondence: T. Bousema, Department of Medical
Microbiology, Radboud University Medical Center, Geert Grooteplein Zuid 26-28, 6500 HB Nijmegen, The Netherlands (teun.
[email protected]).
The Journal of Infectious Diseases® 2016;213:1516–7
© The Author 2016. Published by Oxford University Press for
the Infectious Diseases Society of America. All rights reserved.
For permissions, e-mail [email protected]. DOI:
10.1093/infdis/jiw044
Reply to Goncalves et al
TO THE EDITOR—We agree with Goncalves
et al that our study was restricted to treatment-seeking persons with symptomatic
falciparum malaria. As such, the study
did not assess the relative infectiousness
of what may well be a larger, asymptomatic, and often submicroscopic malaria
transmission reservoir. The absence of
studies on the infectiousness of asymptomatic persons with submicroscopic
malaria in low-transmission settings
yields little evidence for or against targeting these populations as a strategy to
accelerate malaria elimination; indeed,
further evaluation is warranted.
It is important not to conflate asymptomatic malaria with submicroscopic
malaria. Although the cited Thai study
by Pethleart et al measured infectivity
in the community, only those with slidepositive malaria were selected for mosquito feeding [1]. The 2 individuals
identified in the community who were
afebrile but infectious were readily detected by microscopy. We also did not sample those with submicroscopic malaria in
our study, but we detected a substantial
amount of submicroscopic gametocytemia that made little contribution to
human-mosquito transmission.
Those with submicroscopic malaria by
definition harbor submicroscopic gameto-
cytes at low densities, lower than those
seen in asymptomatic but patent infections. In a large survey in Papua New
Guinea that used both microscopic and
molecular detection of malaria, symptomatic persons were more likely to be
gametocytemic, and patent infections overall showed a 6-fold increase in gametocyte
density, as measured by quantitative polymerase chain reaction (PCR), compared
with submicroscopic infections [2]. The
large epidemiological study in Cambodia,
Vietnam, and the Thailand-Myanmar border cited used high-volume ultrasensitive
PCR to detect submicroscopic malaria:
the 20% of individuals identified as harboring parasites averaged a parasite density
of only 5 parasites/µL [3, 4]. Perhaps, then,
it is not that surprising that among the
5000 residents sampled, not a single person had microscopic gametocytemia, the
group that we identified as being >20fold more infectious and infected >200
times more mosquitoes than their counterparts with either none or only submicroscopic gametocytes.
This latter cited study was unable to
screen 28% of residents, many because
they were away. As discussed by Goncalves
et al, it is an open question whether the
relative numbers of those with submicroscopic gametocytes and the potentially
longer duration of their infection led to
a substantial contribution to the infectious reservoir. Ultimately, it seems that
the coverage of malaria-elimination interventions and access by hard-to-reach
populations may be more important than
the degree of sensitivity offered by advanced molecular detection methods.
Finally, we wholeheartedly agree that
membrane feeding at a single time point
cannot be the only measure of the
infectious reservoir. In addition to sampling asymptomatic and submicroscopic
infections, data on the duration of infec-
tiousness and mosquito exposure in different populations are needed to better
guide our understanding of the infectious
reservoir [5].
Notes
Financial support. This work was supported
by the Armed Forces Health Surveillance Center/
Global Emerging Infections Surveillance and Response and the National Institute of Allergy and
Infectious Diseases (grant K08 AI110651 to
J. T. L.).
Potential conflicts of interest. All authors:
No reported conflicts. All authors have submitted
the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors
consider relevant to the content of the manuscript have been disclosed.
Jessica T. Lin,1 Steven R. Meshnick,2
David L. Saunders,3 and Chanthap Lon4
1
Division of Infectious Diseases, School of Medicine, and
Department of Epidemiology, Gillings School of Global Public
Health, University of North Carolina, Chapel Hill; 3Department
of Immunology and Medicine, Armed Forces Research Institute
of Medical Sciences, Bangkok, Thailand; and 4Armed Forces
Research Institute of Medical Sciences, Phnom Penh,
Cambodia
2
References
1. Pethleart A, Prajakwong S, Suwonkerd W, Corthong
B, Webber R, Curtis C. Infectious reservoir of Plasmodium infection in Mae Hong Son Province,
north-west Thailand. Malar J 2004; 3:34.
2. Koepfli C, Robinson LJ, Rarau P, et al. Blood-stage
parasitaemia and age determine Plasmodium falciparum and P. vivax gametocytaemia in Papua New
Guinea. PLoS One 2015; 10:e0126747.
3. Imwong M, Nguyen TN, Tripura R, et al. The epidemiology of subclinical malaria infections in SouthEast Asia: findings from cross-sectional surveys in
Thailand-Myanmar border areas, Cambodia, and
Vietnam. Malar J 2015; 14:381.
4. Imwong M, Stepniewska K, Tripura R, et al. Numerical distributions of parasite densities in asymptomatic malaria. J Infect Dis 2016; 213:1322–9.
5. Stone W, Gonçalves BP, Bousema T, Drakeley C.
Assessing the infectious reservoir of falciparum malaria: past and future. Trends Parasitol 2015; 31:
287–96.
Received and accepted 25 January 2016; published online 9
February 2016.
Correspondence: J. T. Lin, UNC Division of Infectious
Disease, 130 Mason Farm Rd, Ste 2115, CB 7030, Chapel
Hill, NC 27599-7030 ([email protected]).
The Journal of Infectious Diseases® 2016;213:1517
© The Author 2016. Published by Oxford University Press for
the Infectious Diseases Society of America. All rights reserved.
For permissions, e-mail [email protected]. DOI:
10.1093/infdis/jiw045
CORRESPONDENCE
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JID 2016:213 (1 May)
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