News&Comment TRENDS in Parasitology  Vol.17 No.7  July 2001 313
Letters
The importance of malaria and found wide variation in their exposed to different levels of malariaconclusions. The differences could present transmission1 and are associated with
strict patient true geographical variation caused either different cytokine profiles2. In fact,
definitions in studies by transmission pattern or by host and probably both malarial anaemia andparasite genetics, or both. Another cerebral malaria should be further
of malaria important reason for the variation is, subdivided into distinct entities3,4
pathogenesis however, ill-defined patient groups that (B.A.Astrup et al., unpublished). We thushave not been designed specifically to propose that severe malaria should not be
address the questions raised by the studies. studied as one disease entity, and that
Most clinical studies of malaria The bulk of evidence suggests that the careful and uniform case definitions are
pathogenesis in humans are performed as different complications of malaria differ in crucial for studies of malaria pathogenesis.
cross-sectional studies comparing different pathogenesis, management and prognosis. It is also problematic to use so-called ‘mild’
patient categories. We have looked at Malarial anaemia and cerebral malaria malaria as controls. Mild malaria usually
studies of similar clinical manifestations of affect different age groups of children denotes patients with short symptom
Box 1.Guidelines for the design of cross-sectional studies of malaria pathogenesisa
It must be malaria Severity must be quantified in order to compare with other
(1) Malaria parasites must be evident investigations
Asymptomatic infections are common in endemic areas • Use standard coma scales, that is Blantyre coma scale for
• Define cut-off level for parasitaemia above usual asymptomatic children and Glasgow coma scale for adults. 
infections. Patients in coma must be truly unrousable
Some complications, for example malarial anaemia, might occur • Allow 60 min after convulsions for the patient to regain
late, even after parasite clearance consciousness and give diagnostic glucose bolus.
• Design studies longitudinally to follow progression from early Several mechanisms might cause the syndrome cerebral malaria
stage with overt parasitaemia, or • Improve case definitions by characterization of seizures
• Use other parameters to show recent malaria infection, for (electroencephalogram if possible), measurement of cerebral
example pigment or antigen detection. blood flow (if possible), determination of acid–base status,
(2) Characteristic febrile illness must be documented spinal fluid investigations, etc.
Fever fluctuates and might be affected by antipyrexic drugs (3) Malarial anaemia 
• Define fever as axillary temperature >37.5°C measured within Severity of the anaemia must be well defined
24 h of admission. • Define severe anaemia as haemoglobin (Hb) <5 g dl−1 and
(3) Exclude other aetiologies to the findings specify Hb of control groups. 
Asymptomatic malaria infections might coincide with other In most malaria endemic areas, patients with confounding
infections to mimic acute malaria factors, such as nutritional deficiency and concomitant helminth
• Exclude common febrile illnesses, for example respiratory infestations, cannot be excluded
tract infection, gastro-enteritis, urinary tract infection, • Omit ‘grey zones’ by comparing groups with Hb values that are
meningitis, etc. separated by an interval of at least 1 g dl−1.
Unrelated conditions might cause complications similar to those Malarial anaemia might be associated with acute or chronic
of severe malaria infection or cerebral malaria
• Exclude common causes of coma in studies of cerebral malaria, • Attempt to group patients accordingly, or
for example trauma, epilepsia, etc. • Follow patients longitudinally to identify factors associated with
• Exclude common causes of anaemia in studies of malarial progression to anaemia.
anaemia, for example nutritional deficiencies,
haemoglobinopathies, bleeding, hook worm infestation, etc. Controls must be relevant to the hypothesis
(see below). (1) Control groups must be comparable with regard to
parameters that are not studied
The studied syndrome must be well defined Lack of matching might result in comparison of incomparable
(1) General patients, for example early and late stage
Severe malaria syndromes have different pathogenesis • Compare patients who have similar grades of parasitaemia,
• Avoid pooling patients into one group with ‘severe malaria’. temperature, symptom duration, etc. and differ only in the
Certain indicators of severity, such as hyperparasitaemia or studied clinical syndrome.
hyperpyrexia, do not induce a specific clinical picture Too careful matching might hide true differences, for example
• Restrict comparisons to syndromes that are likely to have age-dependent differences hidden by age matching
uniform pathogenesis, or • Select meaningful criteria for matching.
• Study the effect of such indicators in longitudinal studies.
(2) Cerebral malaria aText in italics denotes a problem followed by suggested solutions in roman.
http://parasites.trends.com   1471-4922/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.  
314 News&Comment TRENDS in Parasitology  Vol.17 No.7  July 2001
duration and low parasitaemia. We find it References
more relevant to compare patients with 1 Snow, R.W. et al. (1997) Relation between severe
similar degree of infection but with a malaria morbidity in children and level of 9
Plasmodium falciparum transmission in Africa. 8
different clinical outcome. 7Lancet 349, 1650–1654 6
Guidelines for optimizing cross-sectional 2 Kurtzhals, J.A.L. et al. (1998) Low plasma 54
studies of malaria pathogenesis are given in concentrations of interleukin 10 in severe 3
2
Box 1. Our three main points are: (1) it must malarial anaemia compared with cerebral and 1
be malaria; (2) the clinical syndrome must uncomplicated malaria. Lancet 351, 1768–1772 0
3 Abdalla, S. et al. (1980) The anaemia of P.
be well defined; and (3) controls must be falciparum malaria. Br. J. Haematol. 46, 171–183 Year
relevant to the raised hypothesis. In some 4 Marsh, K. et al. (1996) The pathogenesis of severe TRENDS in Parasitology
cases, the scope of a study requires malaria in African children. Ann. Trop. Med.
deviation from the guidelines. One example Parasitol. 90, 395–402 Fig. 1. Human hydatidosis morbidity in Bulgaria from
is studies of bacteriaemia complicating 1991 to 2000.
Plasmodium falciparum malaria, in which
case, exclusion of other infections is New trends in large numbers of stray dogs and humanobviously not applicable. In such cases, it is habits, such as slaughterhouses permitting
important to explain why standard parasitism in Bulgaria dogs access to infested viscera, feeding of
definitions have not been followed and to dogs with condemned offal that harbours
provide the necessary clinical information A rise of prevalence and incidence rates of cysts and insufficient health education1–5.
to allow comparisons with other studies. parasitic diseases in Bulgaria during the The situation urgently requires the revival
It is unfortunate that many studies have past decade1–3 has led to an increase in of a national control programme.
not adhered to these basic principles of their public health importance. The data From 1991 to 2000, there was a total of
patient selection. The most common reason presented here, regarding parasitic 96 outbreaks of trichinellosis, each of them
is probably that acceptable sample sizes diseases between 1991–2000, were involving 5–250 patients1–4,6. This is a
cannot be obtained within a specified time collected by the Departments of Medical substantial rise compared with the 50-year
in most study sites. However, even if Parasitology at District Hygiene period from 1922 to 1974, when 38
sample sizes become smaller, the use of a Epidemiological Inspections (DHEI) and outbreaks were reported, involving 726
more specific read-out system is likely to submitted for annual analysis to the symptomatic patients that resulted in 17
give clearer results. Another reason is that Bulgarian Ministry of Health and the fatalities (G. Genov, op. cit.). From 1991 to
laboratory scientists often receive clinical National Centre of Infectious and 2000, the number of infected people
samples without direct involvement in the Parasitic Diseases, Sofia, Bulgaria. displaying mild to severe symptoms also
characterization of the patient groups. A increased to 1654 cases. Two out of 5683
close collaboration between clinical staff Indigenous parasitic diseases individuals who consumed infected meat
and biomedical scientists is essential from Indigenous parasitic diseases – zoonoses, died. From 1987 to 1991, 97.4% of 38
the planning through to the execution and such as hydatidosis – have increased in trichinellosis outbreaks in humans were
publication of the studies. Finally, sponsors Bulgaria for the past ten years (Fig. 1). sourced to the wild boar. However, over the
must be convinced of the importance of Between 1950 and 1962, a national past ten years, the source of trichinellosis
long-term funding, as the only way to programme for surveillance and control of infection has been increasingly attributed
obtain reliable results is by taking the hydatidosis resulted in a fall in its to the domestic pig, which accounted for
necessary time. incidence(G. Genov, DSc thesis, Medical 54.2% of 96 outbreaks.
University of Sofia, 1974). However, since Incidence of Taenia saginata infections
Jørgen A.L. Kurtzhals* 1993, there has been a marked rise in in Bulgaria can be classified as moderate,
Dept of Clinical Microbiology, Statens Serum morbidity resulting from hydatidosis. From with rates of 0.9–1.4 per 100 000 people1–3.
Institut, 2300 Copenhagen S, Denmark. 1991 to 2000, 5431 cases were registered by Although, from 1991–2000, no human
*e-mail: jku@ssi.dk DHEI, of which 89.6% consisted of primary infections with T. solium were recorded,
infections (4865 cases) and 10.4% resulted 1–3 cases of human cysticercosis are
Bamenla Q. Goka from postoperative relapses (566 cases). In diagnosed each year. Seroprevalence of
Dept of Child Health, Korle-Bu Teaching some regions of Bulgaria, such as Sliven, toxoplasmosis ranged from 35.2% to 42.2%.
Hospital, PO Box 4236, Accra, Ghana. Burgas, Pazardjick and Chaskovo, Over the same ten-year period, a few cases
morbidity was much higher (15–27 per of cryptosporidiosis (n = 1–3), blastocystosis
Bartholomew D. Akanmori 100 000 people) than the country average (n = 5–20) and visceral leishmaniosis 
Immunology Unit, Noguchi Memorial over the same period (2.4–8.5 per 100 000 (n = 1–3) were also recorded1–3.
Institute for Medical Research, PO Box people). Of all patients in Bulgaria
LG-581, Legon-Accra, Ghana. subjected to surgical treatment, 23% Imported parasitic diseases
(1231 cases) were 0–19 years old1–5. Of the 27 parasitic diseases imported into
Lars Hviid Many factors contribute to the Bulgaria, malaria has the greatest impact
Centre for Medical Parasitology, Dept of perpetuation and spread of the disease, on health1–3,9,10. Of a total of 382 malaria
Infectious Diseases, M7641, Copenhagen such as an absence of a national control episodes registered during the period,
University Hospital (Rigshospitalet), 2100 programme because of the financial 95.0% were imported into Bulgaria from
Copenhagen Ø, Denmark. problems of the country, the presence of countries where malaria is endemic, 4.7%
http://parasites.trends.com   1471-4922/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.  
Morbidity (cases per 100 000)
  1950–
1962
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000