CASE REPORTOpen Access
Idiopathic acute myocarditis during treatment for
controlled human malaria infection: a case report
Maurits PA van Meer1, Guido JH Bastiaens1, Mohamed Boulaksil2, Quirijn de Mast3, Anusha Gunasekera4,
Stephen L Hoffman4, Gheorghe Pop2, André JAM van der Ven3and Robert W Sauerwein1*
A 23-year-old healthy male volunteer took part in a clinical trial in which the volunteer took chloroquine
chemoprophylaxis and received three intradermal doses at four-week intervals of aseptic, purified Plasmodium
falciparum sporozoites to induce protective immunity against malaria. Fifty-nine days after the last administration
of sporozoites and 32 days after the last dose of chloroquine the volunteer underwent controlled human malaria
infection (CHMI) by the bites of five P. falciparum-infected mosquitoes. Eleven days post-CHMI a thick blood smear
was positive (6 P. falciparum/μL blood) and treatment was initiated with atovaquone/proguanil (Malarone®). On
the second day of treatment, day 12 post-CHMI, troponin T, a marker for cardiac tissue damage, began to rise
above normal, and reached a maximum of 1,115 ng/L (upper range of normal = 14 ng/L) on day 16 post-CHMI.
The volunteer had one ~20 minute episode of retrosternal chest pain and heavy feeling in his left arm on day 14
post-CHMI. ECG at the time revealed minor repolarization disturbances, and cardiac MRI demonstrated focal areas
of subepicardial and midwall delayed enhancement of the left ventricle with some oedema and hypokinesia. A
diagnosis of myocarditis was made. Troponin T levels were normal within 16 days and the volunteer recovered
without clinical sequelae. Follow-up cardiac MRI at almost five months showed normal function of both ventricles
and disappearance of oedema. Delayed enhancement of subepicardial and midwall regions decreased, but was
still present. With the exception of a throat swab that was positive for rhinovirus on day 14 post-CHMI, no other
tests for potential aetiologies of the myocarditis were positive. A number of possible aetiological factors may
explain or have contributed to this case of myocarditis including, i) P. falciparum infection, ii) rhinovirus infection,
iii) unidentified pathogens, iv) hyper-immunization (the volunteer received six travel vaccines between the last
immunization and the CHMI), v) atovaquone/proguanil treatment, or vi) a combination of these factors. Definitive
aetiology and pathophysiological mechanism for the myocarditis have not been established.
Keywords: CHMI, Myocarditis, Troponin T, MRI, Malaria
Controlled human malaria infections (CHMIs) have been
used for nearly a century for treatment of neurosyphilis
and for assessing interventions like drugs and vaccines for
treating and preventing malaria. However, the modern era
of CHMIs began in the mid 1980s, when laboratory reared
Anopheles sp. mosquitoes were infected by feeding on
cultures of Plasmodium falciparum-infected blood .
During the past three decades CHMI has been shown
safe, well-tolerated and useful in evaluation of potential
new anti-malarial drugs and vaccines . After expos-
ure to bites of laboratory-reared mosquitoes infected
with P. falciparum sporozoites (PfSPZ) clinical symptoms
and signs of malaria are generally mild to moderate and
last for a few days. The most commonly reported
symptoms are headache, fever, myalgia and fatigue, and
common laboratory abnormalities include clinically
insignificant thrombocytopaenia and leukopaenia [3,4].
Subjects, who undergo CHMI, are closely monitored
and immediately treated with anti-malarials upon de-
tection of parasitaemia. Due to frequent and intense
clinical monitoring, initiation of treatment almost al-
ways occurs at parasite densities of less than 0.001%
and often at 0.0001% , a density which is more than
* Correspondence: Robert.Sauerwein@radboudumc.nl
1Department of Medical Microbiology, Radboud University Medical Center,
Nijmegen, The Netherlands
Full list of author information is available at the end of the article
© 2014 van Meer et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
van Meer et al. Malaria Journal 2014, 13:38
1,000-fold lower than parasite densities associated with
causing severe malaria.
Immunization of volunteers taking chloroquine chemo-
prophylaxis with whole PfSPZ administered by mosquito
bites resulted in complete and long-lasting protection
against CHMI with P. falciparum-infected mosquitoes
[6,7]. This immunization approach is called “ChemoPro-
phylaxis with Sporozoites” (CPS). Since CPS depends
on inoculation of PfSPZ by mosquito bites, it cannot
be an implementable vaccine. Recently, subjects were
infected by needle and syringe inoculation of aseptic,
purified, cryopreserved PfSPZ, a product called PfSPZ
Challenge [8,9]. Subsequently, a clinical trial was initiated
in which volunteers taking chloroquine chemoprophylaxis
were injected intradermally (ID) at four-week interval
with PfSPZ Challenge, an approach called the PfSPZ-
CVac approach (=PfSPZ Chemoprophylaxis Vaccine),
and then underwent CHMI.
Here, a very probable case of acute myocarditis is
described in a volunteer who had taken chloroquine
chemoprophylaxis, was inoculated three times at four-
week intervals with PfSPZ Challenge, received six travel-
related routine vaccines after this immunization procedure,
had CHMI by the bites of five PfSPZ-infected mosquitoes
8.5 weeks after the last dose of PfSPZ Challenge and
4.5 weeks after the last dose of chloroquine, had a sore
throat on day 9 after CHMI, developed P. falciparum para-
sitaemia that was treated 11 days after CHMI, and had
asymptomatic initial elevation of troponin T levels 12 days
A 23-year-old healthy male volunteer was enrolled in a
double blind, randomized, controlled trial that assessed
the safety, tolerability, and protective efficacy against
CHMI by PfSPZ-infected mosquitoes of intradermal ad-
ministration of aseptic purified cryopreserved PfSPZ
(PfSPZ Challenge) in volunteers taking weekly 300 mg
chloroquine prophylaxis, the PfSPZ-CVac approach.
His medical history was unremarkable, and he did not
smoke or use illicit drugs. His mother had a history
of hypertension and his paternal grandfather had a history
of heart valve defects and a possible myocardial infarc-
tion at the age of 70. At inclusion, physical examination
was within normal limits with a blood pressure of 139/
76 mmHg, heart rate of 55 beats per minute and a body
mass index of 20.2 kg/m2. Electrocardiography (ECG)
showed a commonly seen normal variant of incomplete
right bundle branch block (see Additional file 1). Standard
laboratory tests at inclusion were normal (seeTable 1).
From October to December 2012, he received three
intradermal injections at four-week intervals of 7.5 ×104
PfSPZ of PfSPZ Challenge (PfNF54) diluted in phosphate
buffered saline with 1% human serum albumin. From
day 3 until day 8 after the first immunization he reported
a sore throat and symptoms of a common cold (i.e., stuffy
nose and coughing) with mild chills for a few hours. No
complaints were reported after the second and third
immunizations. No clinically significant laboratory abnor-
malities were found during the immunization period.
Fifty-nine days after the third and last immunization
and 32 days after his last dose of chloroquine, he under-
went CHMI by the bites of five P. falciparum-infected
mosquitoes (PfNF54). On day 9 post-CHMI he com-
plained of a sore throat. On day 11 post-CHMI his thick
blood smear became positive (6 P. falciparum/μL blood;
0.00012% infected erythrocytes) and standard treatment
with Malarone® (1,000 mg atovaquone plus 400 mg pro-
guanil once daily for three days) was initiated. Retro-
spective assessment of parasitaemia by quantitative
polymerase chain reaction (qPCR) revealed 13,293 para-
sites/mL (0.00026% infected erythrocytes) on day of
thick smear positivity. On that day he complained of
minor chills and headache for a few hours with a highest
recorded sublingual temperature of 37.5°C. Platelet and
lymphocyte counts decreased to 97 ×109/L (normal
range =141 – 400 ×109/L) and 0.60 ×109/L (normal
range =1.0 – 3.5 ×109/L), respectively, as often seen in
malaria positive individuals [5,10]. The level of troponin
T by a highly sensitive assay was normal (i.e., 8 ng/L;
upper limit of normal =14 ng/L). Troponin T is a spe-
cific marker for myocardial tissue damage.
On the second day of Malarone treatment (day 12
post-CHMI) the troponin T level was elevated at 45 ng/L
and increased to 63 ng/L in the evening. No abnormal-
ities were seen on ECG. Apart from mild headache and
fatigue on the following day (day 13 post-CHMI) the
volunteer was asymptomatic, but the troponin T was
197 ng/L in the morning and 299 ng/L in the afternoon.
The blood pressure was 114/60 mmHg and the ECG
revealed mild repolarization disturbances with diffuse
ST-T-segment elevation, suggestive of pericarditis (see
Additional file 2). The echocardiogram showed mild
hypokinesia of the inferior wall and a slightly dimin-
ished global left ventricle (LV)-function (calculated LV
ejection fraction of 53%; normal range for a young man
is > 55%). Malarone treatment was completed and qPCR
for P. falciparum was negative on day 13 post-CHMI.
Although the subject did not have any cardiac or chest
symptoms, he was hospitalized at the cardiology depart-
ment according to safety protocol for telemetric ECG-
monitoring and follow-up of troponin T levels.
That night at ~01:00 AM he experienced retrosternal
pain and a heavy feeling in his left arm. After appro-
ximately 10 minutes sublingual nitroglycerin spray was ad-
ministered; the chest pain did not disappear immediately,
but only 10 minutes after administration of nitroglycerin.
The pain was not related to breathing and there were no
van Meer et al. Malaria Journal 2014, 13:38
Page 2 of 8
concomitant complaints or signs of dyspnoea, pyrosis or
ructus. The subject never had another episode of chest
pain. Cardiac MRI several hours later on day 14 post-
CHMI showed: i) slightly increased T2-weighted signal in-
tensity in the basal- and mid-inferolateral and partly in the
mid-anterolateral myocardial segments, matching minor
oedema (see Figure 1A); ii) focal areas of subepicardial and
midwall delayed enhancement in the basal- and mid-
inferior and basal- and mid-inferolateral segments after ad-
ministration of gadolinium contrast (see Figure 1B and C);
iii) hypokinesia basal- and mid-inferior and mild hypokine-
sia basal- and mid-inferolateral. These findings were in-
terpreted as indicative of myocarditis. Treatment was
started on day 14 post-CHMI with a beta-blocker, metopro-
lol (25 mg twice daily), to reduce the chance of cardiac
arrhythmia and according to the treatment guidelines for
patients with reduced LV-function.
Troponin T levels continued to rise with a peak of
1,115 ng/L on day 16 after CHMI. The following days
troponin T decreased and eventually returned to normal
16 days after initial increase, corresponding to 28 days
post-CHMI. Creatine kinase (CK) showed a similar
pattern of rising and falling, but returned to normal on
day 16 post-CHMI. A biochemical marker of cardiac
wall stress, N-terminal pro-hormone brain natriuretic
peptide (NT-proBNP), was slightly elevated on days 15
and 17 post-CHMI, but was normal on day 20 post-
CHMI (see Table 1). A limited rise and fall of aspartate
aminotransferase (AST) and lactate dehydrogenase (LDH)
were found. The nonspecific marker for increased coagu-
lation and inflammation, D-dimer, remained within the
normal range and was only minimally elevated on the first
day after thick smear positivity. Similarly, the inflamma-
tory acute-phase protein, C-reactive protein (CRP) was
only slightly elevated on days 13, 14, and 15 after CHMI
(see Table 1). Four days after admission (day 17 post-
CHMI) ECG and echocardiogram had normalized (see
Additional file 3 and calculated LV ejection fraction was
62%; normal range is>55%) and the volunteer was
Apart from the single short episode of chest pain and
a longer period of fatigue with occasional mild head-
ache during and shortly after hospitalization, no other
complaints were reported. The fatigue diminished after
Table 1 Laboratory findings
Haematology and biochemistry testsNormal rangeInclusionC +11C +12 C +13C +14 C +15C +16 C +17C +20 C +28
Haemoglobin (mmol/L) 8.5 – 10.810.1 9.410.2 188.8.131.52.2 8.0 9.59.6
0.41 – 0.530.47 0.430.47 0.430.380.370.38 0.370.440.44
3.6 – 10.74.94.23.3 184.108.40.206 4.04.8 7.7 5.4
2.0 – 7.52.16 3.041.851.77 1.262.12
1.0 – 3.5 2.050.60 0.790.88 1.132.57
0.3 – 1.00.430.48 0.520.470.550.47
≤ 0.64 0.210.080.080.100.090.21
< 0.10 0.03 0.030.02 0.020.03 0.05
141 – 400138 9794 8489 108123 129200 162
Sodium (mmol/L) 135 – 143139 138 142
Potassium (mmol/L)3.7 – 5.0 3.84.03.8
Creatinine (μmol/L) 60 – 13287 8274 8380 7675
Urea nitrogen (mmol/L)2.5 – 8.1 220.127.116.11
Alkaline phosphatase (U/L)
≤ 126668284 76 7776
Aspartate aminotransferase (U/L)
≤ 381649 81664132
Alanine aminotransferase (U/L)
≤ 4923 3342374140
Lactate dehydrogenase (U/L)
≤ 250110142181222 316262 258222154
γ Glutamyl-transferase (U/L)
Creatine Kinase (U/L)
≤ 170175284501320 133 70
Troponin T (ng/L)
NT-proBNP (pg/mL)< 8819712867
≤ 10 2216118< 5< 5
≤ 500< 500< 500570< 500< 500< 500 < 500< 500< 500
Clinical laboratory findings at inclusion (day before the start of the trial), on day of thick smear positivity (C+ 11, day 11 after CHMI) and subsequent days 12, 13,
14, 15, 16, 17, 20, and 28 after CHMI.
van Meer et al. Malaria Journal 2014, 13:38
Page 3 of 8
halving the dose of metoprolol to 25 mg once daily on day
23 post-CHMI. The remaining mild fatigue completely
disappeared three weeks later on day 44 post-CHMI. After
discharge the volunteer did not complain about occasional
mild headache anymore.
The volunteer received pre-travel vaccines for diph-
theria, tetanus, polio, typhus, hepatitis A and hepatitis B
14 days after the third injection of PfSPZ Challenge
(46 days before CHMI). He had booster vaccinations for
hepatitis A and B 40 days after the third injection (20 days
Polymerase chain reaction (PCR) analyses of throat
smear, faeces and whole blood were carried out for
viruses and bacteria known to cause myocarditis (see
Table 2). Throat smear PCR was positive for rhino-
virus; all other PCR results were negative (Table 2).
Virological, bacteriological and parasitological serology
was performed on samples obtained three weeks before
inclusion and on day 17 post-CHMI (see Table 3) with
repeat testing 18 days later (day 35 post-CHMI and
23 days after first elevation of troponin T). All sero-
logic results were negative. Furthermore, urine toxicol-
ogy screening for amphetamine-derivatives, cocaine,
cannabinoids, diazepam, methadone, tramadol hydro-
chloride, and opiates was negative on day 17 after
Figure 1 Cardiac MRI on day 14 and 153 after CHMI. (A) Slightly increased T2-weighted signal intensity was observed in the basal-inferolateral
segment of the left ventricle on day 14 after CHMI (C+14), which had disappeared on day 153 after CHMI (C+153); visualized on the short-axis dark
blood STIR (short inversion time inversion recovery) recordings. (B and C) After administration of 15 mL gadolinium contrast subepicardial and midwall
delayed enhancement was observed in the basal-inferolateral and basal-inferior segments of the left ventricle on day C+14, which had decreased on
day C+153; visualized on the short-axis (B) and the 4-chamber (C) PSIR (phase sensitive inversion recovery) recordings.
van Meer et al. Malaria Journal 2014, 13:38
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At almost five months after the first MRI, repeat
cardiac MRI demonstrated good function of the left
ventricle (calculated LV ejection fraction of 67%) with
persistence of mild hypokinesia in the mid-inferior and
mid-inferolateral segments of the left ventricle. The
oedema had disappeared completely (see Figure 1A)
and concomitantly the delayed enhancement had de-
creased, mostly in the basal-inferolateral segment (see
Figure 1B and C). However, patchy midwall and subepi-
cardial delayed enhancement was still present in four
myocardial segments (i.e., the basal-inferolateral, mid-
inferolateral, basal-inferior, and mid-inferior segments).
Follow-up ECG did not show any abnormalities except
for a minimally widened QRS complex compared to
the pre-trial ECG and the persistence of incomplete
right bundle branch block (see Additional file 4). In
addition, ECG during a cardiac stress test did not show
ST-T-segment changes, rhythm abnormalities, or other
changes with respect to the pre-trial ECG. The cardiac
stress test used a cycling protocol starting at 50 watt and
with increasing steps of 20 watt per minute. He reached a
Table 2 PCR results for known infectious pathogens of
Throat smear tested by PCR for:
Adenovirus, Bocavirus, Coronavirus,
Chlamydia Psittaci, Enteroviruses,
Parechovirus, Parainfluenza 1 – 4,
Rhinovirus, Respiratory Syncytial Virus,
and Influenza A and B
Faeces tested by PCR for:
Adenovirus (Adenotype 40 and 41),
Astrovirus, Bocavirus, Enteroviruses,
Norovirus, Parechovirus, Rotavirus,
Blood tested by PCR for:
Varicella Zoster Virus, Parvovirus,
Epstein-Barr Virus, Cytomegalovirus,
Q fever, and HIV load
PCR results for known virological and bacteriological causes of myocarditis
based on samples taken on day 14, 15, and 17 after CHMI (C+ 14, C + 15,
and C +17, respectively).
Table 3 Serology results for known infectious pathogens of myocarditis
Sera tested for antibodies to:Screening visit (paired with C+17)C+ 17 C+17 (paired with C+35) C+35
Echovirus pool20 < 10 (negative) < 10 (negative) 10
(Types 4, 6, 9, 14, 24, and 30)
Coxsackie virus pool 20 1010 20
(Types A9, B1 – B6 )
Poliovirus 2010 2040
Adenovirus Ig 20< 10 (negative)20 20
Parvovirus IgG 6464
Mycoplasma pneumoniae IgMnegative negativenegative
Mycoplasma pneumoniae IgAnegative negativenegative
Mycoplasma pneumoniae Ig< 10 (negative) < 10 (negative)< 10 (negative)< 10 (negative)
Chlamydia including Psittacosis Ig< 10 (negative)< 10 (negative) < 10 (negative) < 10 (negative)
Q fever phase 2 IgM negativenegativenegative
Q fever Ig< 10 (negative)< 10 (negative) < 10 (negative)< 10 (negative)
Hepatitis B s-antigen negative negative
Hepatitis B anti-HBcnegative negative
Hepatitis C Ignegativenegative
Borrelia blot IgMnegativenegative
Borrelia blot IgGnegative negative
Legionella serotype 1 – 7 IgMnegative negative negative
Legionella serotype 1 – 7 IgG negative negativenegative
Syphilis IgG negative negative
Toxoplasma IgG negativenegative
Serology results for known virological, bacteriological and parasitological causes of myocarditis based on samples taken at the screening visit, on day 17, and 35
after CHMI (C +17 and C+ 35, respectively). Paired serologic analysis was performed with serum drawn at the screening visit (three weeks before the start of the
trial) for a number of pathogens. To detect potential delayed immune responses serologic analysis was repeated on day C +35. Again, paired serologic analysis
was performed with serum drawn on day C + 17 for a number of pathogens.
van Meer et al. Malaria Journal 2014, 13:38
Page 5 of 8
maximally achieved power of 270 watt (i.e., 122% of ex-
pected for his age group and gender). He had an adequate
increase in blood pressure and heart rate. His heart rate
pressure product was 35,854 mmHg/min (normal is>
25,000 mmHg/min). Metoprolol 25 mg once daily was
stopped and the volunteer has remained without com-
plaints in good condition.
Clinically suspected acute myocarditis with typical MRI
characteristics is reported in a healthy volunteer partici-
pating in a PfSPZ-CVac approach phase 1 clinical trial.
The first myocarditis manifestations occurred 71 days
after the last dose of PfSPZ Challenge, 44 days after the
last dose of chloroquine, 57 and 31 days after receiving
pre-travel vaccines, 12 days after CHMI by P. falci-
parum-infected mosquito bites, three days after the onset
of a sore throat, and one day after diagnosis of P. falci-
parum malaria and initiation of treatment for malaria.
The retrosternal chest pain , kinetics of increased
troponin T plasma concentrations, ECG and echocar-
diogram findings, and MRI findings, which are consist-
ent with the guidelines of the International Consensus
Group on MR Diagnosis of Myocarditis , support
the diagnosis of acute myocarditis. Moreover, improved
myocardial function, disappearance of oedema and re-
duced delayed enhancement after almost five months cor-
respond to the natural course of acute myocarditis; the
residual delayed enhancement is consistent with contrast
retention in fibrous tissue . In addition, BNP and NT-
proBNP were temporarily elevated and their elevation
has also been found in patients with myocarditis and is
associated with reduced left ventricular function [14,15].
The occurrence of the cardiac event relates in time with
residual parasitaemia during curative Malarone treatment
post-CHMI that might be suggestive of a causal relation-
ship. A few cases of malaria and concomitant myocarditis
have been reported in the literature, albeit restricted to pa-
tients with severe or fatal infection with P. falciparum
[16-22] and Plasmodium vivax malaria . In literature,
myocarditis has never been reported in patients with un-
complicated P. falciparum malaria, even in those patients
who present with P. falciparum parasite densities 20 to 30
times higher than the parasite density in this volunteer. In
addition, troponin T plasma concentrations have never
shown elevations above background in an unselected
group of 167 volunteers when daily measured after CHMI
using a highly sensitive assay (personal communication by
RW Sauerwein (Radboud university medical center, The
Netherlands)). Consistent with this finding, troponin T
was very rarely (0.6%) elevated when assessed retrospect-
ively in patients with uncomplicated P. falciparum malaria
. In contrast, 31 – 80.5% of African children with severe
and/or fatal P. falciparum malaria exhibited high to very
high levels of circulating cardiac proteins indicating myo-
cardial injury and impaired left ventricular function .
Previously, a cardiac serious adverse event was re-
ported in a female volunteer who participated in a phase
1 clinical trial in which she was immunized with a sub-
unit, recombinant protein malaria vaccine (PfLSA3),
underwent CHMI by mosquito bites, developed malaria,
and was treated with Riamet® (artemether/lumefantrine)
. She was diagnosed with acute coronary syndrome
two days after completing treatment, but myocarditis
was considered a possible alternative diagnosis. Apart
from one confirmed myocardial infarction in a male
volunteer with an increased cardiovascular risk, who un-
derwent CHMI but did not develop parasitaemia , there
have been no other reports of cardiac complications in the
approximately 2,000 subjects who have undergone CHMI
since the 1986 report by Chulay et al. .
In the current case the cardiac event occurred during
the three days when the subject was receiving curative
Malarone treatment for P. falciparum malaria. There are
no previous data indicating that anti-malarial treatment
with atovaquone/proguanil (Malarone®), or its metabolite
cycloguanil causes myocarditis or any other significant
cardiovascular toxicity . Furthermore, the product
monograph of Malarone does not mention cardiotoxicity
or myocarditis, only palpitations and tachycardia.
The most common cause of acute myocarditis in a
healthy young individual is a viral infection . Numer-
ous infectious pathogens can cause acute myocarditis
[29,30]. Enteroviridae (including Coxsackie B) were re-
sponsible for 25 – 30% of cases in the past , but more
recently, other viruses (including adenovirus, parvovirus
B19, and hepatitis C) have also emerged as important car-
diotropic pathogens . In the current volunteer, diag-
nostic tests for the most common infectious causes of
myocarditis were negative (see Table 2 and 3). However,
negative convalescent antibody titers do not exclude a
post-infectious myocarditis. Furthermore, a throat swab,
taken two days after the initial increase in troponin T
contained rhinovirus, and rhinovirus has been occasionally
associated with myocarditis [33,34]. Noteworthy, rhino-
virus is often detected by PCR in asymptomatic subjects
and a causal inference with symptomatic patients should,
therefore, be made with caution .
The pathogenesis of myocarditis can be due to direct
infection of the myocardium by a replicating pathogen,
the host’s specific immunologic response to such an in-
fection , or a nonspecific immunologic response in a
susceptible individual that could have been triggered in
this case by the malaria infection. In most such cases
one would expect to find markers of inflammation ele-
vated. However, markers for nonspecific inflammation
and haemolysis, D-dimer, CRP, and LDH, were normal
or only slightly elevated when the troponin T levels were
van Meer et al. Malaria Journal 2014, 13:38
Page 6 of 8
highest (see Table 1). Nonetheless, it is possible that an
overall hyperreactivity induced by the six standard vaccines
(i.e., diphtheria, poliomyelitis, tetanus, parenteral typhoid
fever, hepatitis A and hepatitis B) the volunteer received
between the immunization period and CHMI, and the
subsequent CHMI could have generated a hypersensitivity
myocarditis. Such post-vaccination myocarditis has been
rarely reported for the administered vaccines and usually
manifests with fever and/or other nonspecific inflammatory
symptoms within several days of the hyperimmunizations
, which did not occur in this volunteer. Nonetheless,
this explanation cannot be ruled out.
No systemic allergic reactions or local adverse events
have occurred in the 20 volunteers, who have now re-
ceived three intradermal (ID) injections of 7.5 ×104
PfSPZ of PfSPZ Challenge. Moreover, there have been
no systemic allergic reactions among the 184 subjects
who have received single doses of PfSPZ Challenge by
the ID (n = 84), intramuscular (IM) (n = 70), and intra-
venous (IV) (n = 30) routes in order to study the safety
and infectivity of PfSPZ Challenge ([8,9] and personal
communication by SL Hoffman (Sanaria Inc., USA)), or
among the 120 volunteers who have received up to six
doses of 1.35 ×105radiation-attenuated PfSPZ (PfSPZ
Vaccine) ID (n = 40), subcutaneously (SC) (n = 40), or
IV (n=40) [38,39]. Thus, it seems extremely unlikely that
the parenterally administered PfSPZ or the phosphate
buffered saline or human serum albumin with which the
PfSPZ are administered contributed to the myocarditis or
contain an immunologically sensitizing agent.
Myocarditis may also be triggered by toxins, alcohol,
cocaine, chemotherapeutics, antibiotics, metabolic ab-
normalities, and other factors [29,30]. However, the vol-
unteer denied excessive use of alcohol, and urine drug
tests for cocaine, amphetamines and cannabinoids were
negative, making such factors an unlikely explanation.
Alcohol intake was not quantified during follow-up visits
after CHMI, but volunteers were repetitively instructed
to restrict alcohol intake. Since the urine drug test was
performed five days after the first rise in troponin T, the
detection of metabolites of cocaine and amphetamines
after single use is quite limited at this time and could
have been missed .
In conclusion, there are different possible causes for the
myocarditis but a definitive cause in this case cannot be
established. It is also possible that a combination of the
above-discussed potential aetiological factors could have
contributed to the development of this case of acute
Informed consent for publication of this case report was
obtained from the volunteer who participated in this
Additional file 1: Electrocardiogram at screening visit before start
of the clinical trial (10-SEP-2012, 10:59 AM) showing a normal
variant of an incomplete right bundle branch block.
Additional file 2: Electrocardiogram on day 13 after CHMI
(18-FEB-2013, 07:41 PM) showing mild repolarization disturbances
with diffuse ST-T-segment elevation.
Additional file 3: Electrocardiogram on day 16 after CHMI
(21-FEB-2013, 12:13 PM) showing normalization of the repolarization
disturbances compared to the previous ECG of 18-FEB-2013.
Additional file 4: Electrocardiogram on day 153 after CHMI
(08-JUL-2013, 09:48 AM) showing no abnormalities except for the
known incomplete right bundle branch block and a minimally
widened QRS complex compared to the pre-trial ECG.
The authors declare that they have no competing interests. However, SLH
and AG are employees of Sanaria Inc., the manufacturer of PfSPZ Challenge.
MPAvM, GJHB, QdM, and AJAMvdV were clinical investigators. GP and MB
were consultants in cardiology. SLH initiated and coordinated the clinical
trial. AG carried out the regulatory affairs of the clinical trial. RWS was principal
investigator. MPAvM, GJHB, and RWS wrote the paper with comments from the
other authors. All authors read and approved the manuscript.
We thank the Safety Monitoring Committee (T.B. Nutman, P.F. Weller, and A.J.
M. Rennings) for their advice and expert reviews. We thank Dr. Maureen van
der Vlugt for the preparation and interpretation of the MRI-scans. The clinical
trial was financially supported by the Top Institute Pharma grant T4-102.
1Department of Medical Microbiology, Radboud University Medical Center,
Nijmegen, The Netherlands.2Department of Cardiology, Radboud University
Medical Center, Nijmegen, The Netherlands.3Department of General Internal
Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
4Sanaria Inc., Rockville, MD, USA.
Received: 4 November 2013 Accepted: 27 January 2014
Published: 30 January 2014
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Cite this article as: van Meer et al.: Idiopathic acute myocarditis during
treatment for controlled human malaria infection: a case report. Malaria
Journal 2014 13:38.
van Meer et al. Malaria Journal 2014, 13:38
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