INFECTION IN INTERMEDIATE HOST: BLACKWATER 
209 
nuria among the clinical forms of the 
malarial infection . . . (and it) is a phe¬ 
nomenon which may be manifested during 
the course of an active infection as well as 
in one which has spent its course; it is in¬ 
timately related to malaria, but there is no 
direct causal relation between this phenom¬ 
enon and the malarial parasites, such as 
there is, for example, between the coma of 
a pernicious attack and the parasitic inva¬ 
sion of the capillary vessels of the brain. 
Nor do we believe that we can class to¬ 
gether, as some have done, hemorrhagic 
malarial infections in general and hemo¬ 
globinuria. ’ ’ 
The finding of P. vivax and P. malariae 
in blood smears from blackwater fever 
patients has been considered by some work¬ 
ers as evidence against P. falciparum as the 
constant etiological factor. This must be 
regarded as circumstantial evidence. Ross 
(1932) stated that “. . . it would seem that 
too much significance is placed upon the 
species then present as indicating the 
variety of malaria which has led to the 
development of susceptibility.” In this 
connection Boyd and Kitchen (1937f) have 
noted that in induced mixed infections with 
P. falciparum and P. vivax, only P. vivax, 
for example, may be observed in the blood 
smears at a given time even though there 
exists a concurrent P. falciparum infection. 
In addition to this, the hemoglobinuric 
paroxysm may have occurred after clinical 
termination of a falciparum attack and yet 
coincidentally with the appearance of a 
new P. vivax or quartan infection. 
Furthermore, in the majority of black¬ 
water fever attacks, though parasites may 
be demonstrated prior to the paroxysm, 
their incidence in the peripheral blood 
afterwards diminishes rapidly. This also 
could account for the frequent absence of 
P. falciparum. 
Among additional predisposing factors 
in the etiology of hemoglobinuric fever 
there may be considered: (1) Familial 
disposition. Many authors have cited in¬ 
stances in which several members of certain 
families showed a marked tendency to 
develop hemoglobinuria, particularly in 
some cases following the use of small doses 
of quinine. Deaderick (1914), in a study 
of 34 patients, recorded evidence of familial 
tendency. Stephens (1937) concluded, 
“ ‘Disposition,’ whether personal—and 
even hereditary—or familial may involve 
some at present unknown factor, but the 
known factor malarial infection appears 
always to be present.” (2) Age and (3) 
Sex. The reports regarding these two fac¬ 
tors are somewhat conflicting and it would 
seem that they both are subordinate to a 
dominating factor, viz., opportunity for 
exposure to malaria. (4) Deeks and James 
(1911) considered that syphilis was an im¬ 
portant predisposing cause by reason of its 
tendency to provoke relapses of malaria. 
Among the exciting causes of the hemo¬ 
globinuric attack, parturition, over-exer¬ 
tion and fatigue, exposure to cold and 
quinine have been chiefly mentioned. Foy 
and Kondi (1936) could find no evidence 
favoring the existence of hemolytic strains 
of plasmodia or such other specific para¬ 
sites as have also been suggested as etio¬ 
logical factors. Deeks and James (1911) 
felt that malaria should be considered not 
only as a predisposing cause but also as a 
precipitating cause. 
The role of quinine in provoking an at¬ 
tack of hemoglobinuria is a very puzzling 
one. It is a well established fact that very 
small doses of this drug have repeatedly 
been followed by hemoglobinuria in some 
persons. Quinine can be shown to produce 
hemolysis in vitro, but the corresponding 
amount required to do so in vivo could not 
be tolerated by the human organism under 
any circumstances. On the other hand, it 
is known that quinine has been given in 
blackwater fever with impunity. Many 
patients appear to be tolerant of a certain 
dose but exhibit hemoglobinuria when that 
amount is exceeded. The maximum inci¬ 
dence of hemoglobinuria as a reaction to 
quinine appears to occur within six hours 
of administration. 
An excess of lactic acid due to deficient 
oxygenation was advanced by Blacklock 
and Macdonald (1928) as the cause of 
hemolysis in blackwater fever, but Ross 
