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hypoxia, were unsuccessful ( Ross, 1918 ; Howe and Duff, 1946 ). Neverthe-
less, soldiers in field hospitals in the Mediterranean region between 1940
and 1945 (who had acquired P. vivax in North Africa or Italy) were appar-
ently more likely to experience vivax malaria (presumably a relapse) if they
had pneumonia or hepatitis compared with trench foot - a local rather than
systemic illness ( Levine, 1963 ; McLester, 1945 ). In a series of children seen
daily for over 18 months on the Thai-Burmese border during a study of the
SPf66 malaria vaccine ( Nosten et al., 1996 ), P. vivax episodes were associated
with malaria, but not with minor illnesses (S Lee; personal communication),
suggesting that a substantial systemic stimulus is required for activation. In
endemic areas of South East Asia, immunity to P. vivax is acquired more rap-
idly than to P. falciparum partly because of relapses, so in adults, the systemic
illness associated with acute falciparum malaria may be a greater stimulus to
P. vivax hypnozoite activation than acute vivax malaria.
How can periodicity in vivax relapse be explained? Periodicity can
be generated in biological systems in several ways. Illness, generally (and
the associated cytokine responses), or malaria, specifically, could provide
the activating or inhibitory necessary stimuli to generate periodic relapses
in vivax malaria. It is suggested ( White, 2011 ) that the illness associated
with the infection itself is the hypnozoite activator that results in P. vivax
relapses ( Fig. 2.8 ). Each symptomatic episode provides an activation stimu-
lus, which may give rise to the next relapse. Iterations continue until the
stimulus fails or there are no more hypnozoites. A simple clock mecha-
nism with a single unimodal distribution of latencies does not explain the
observed phenomena. Equally, a multiplicity of different latencies with a
single harmonic seems more complex and does not explain the efficient
use of relatively small sporozoite inocula (median ∼10 sporozoites). For
efficient yet periodic activation of small numbers of hypnozoites (i.e. so
that they do not all activate together), it is necessary to hypothesise either
a negative feedback mechanism, with illness perhaps being the negative
feedback, or a relatively broad temporal distribution of latencies, and a
low individual susceptibility to activation. Either results in several relapses at
regular intervals, each activated by the preceding illness. The proportion
of susceptible hypnozoites is fractional, at least initially, which is consis-
tent with the observed fixed proportions of patients who experience mul-
tiple relapses ( Fig. 2.5 ). It may leave behind unactivated (but activatable)
hypnozoites, which remain dormant until either they die (when the host
hepatocyte dies), or they are activated by a systemic illness such as malaria.
The size of this 'bank' depends on the intensity of exposure. This would
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