clin infect dis. 2001 schwartz 1774 7

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1774 CID 2001:33 (15 November) BRIEF REPORTS

B R I E F R E P O R T

Age as a Risk Factor for Severe

Plasmodium falciparum Malariain Nonimmune Patients

Eli Schwartz,1,2 Siegal Sadetzki,3,4 Havi Murad,3,4 and David Raveh5

1Center for Geographic Medicine and Departments of 2Medicine C and 3Clinical

Epidemiology, Chaim Sheba Medical Center, Tel Hashomer, 4Sackler School

of Medicine, Tel Aviv University, Tel Aviv, and 5Infectious Diseases Unit,

Shaare Zedek Medical Center, Jerusalem

In this nationwide, cross-sectional study, we evaluated the

influence of age and other factors that affect clinical outcome

of Plasmodium falciparum malaria in nonimmune patients.

Of 135 patients with P. falciparum malaria, 84 (62%) were

!40 years old, and only 5% of the patients in this age group

developed severe malaria, compared with 18% of the subjects

who were 40 years of age (odds ratio, 4.29); moreover, all

deaths occurred in the latter group. Male subjects did not

differ from female subjects with regard to severity of disease.

Malaria is still one of the most prevalent diseases, with an

infected population of 300500 million and 1.53.5 million

deaths reported annually [1]. The major killer is Plasmodium

falciparum, which causes multiorgan involvement and, in the

absence of prompt and appropriate treatment, is associated withhigh mortality rates. The highest mortality rate attributable to

malaria in endemic regions is among children, probably because

of their lack of immunity. Conversely, native adults in countries

where malaria is endemic can be subclinical carriers of malaria

because of a natural immunity acquired during their childhood.

The increasing number of persons who travel from indus-

trialized countries to areas where malaria is endemic has in-

creased the rate of imported malaria, mainly by nonimmune

adult populations [2]. Conflicting data exist regarding P. fal-

ciparum malaria among travelers in the older-age group; there

is no concurrence as to whether the course of the disease tends

to be more severe among older travelers than it is among

younger travelers [3, 4]. The aim of the present investigation

Received 2 January 2001; revised 19 April 2001; electronically published 12 October 2001.

Reprints or correspondence: Dr. Eli Schwartz, Center for Geographic Medicine and Dept.

of Medicine C, Chaim Sheba Medical Center, Tel Hashomer, 52621 Israel (elischwa

@post.tau.ac.il).

Clinical Infectious Diseases 2001;33:17747

2001 by the Infectious Diseases Society of America. All rights reserved.

1058-4838/2001/3310-0026$03.00

was to evaluate the influence of age and other factors that affect

the severity of P. falciparum malaria among all Israeli travelers

with malaria.

Patients and methods. The target population for this re-

port included all cases of P. falciparum malaria diagnosed from

1994 through 1999 among nonimmune travelers in Israel. Im-

migrants and foreign visitors from endemic countries were ex-

cluded. The data were obtained from the Department of Ep-

idemiology, Israel Ministry of Health (Jerusalem), to which, by

law, all cases of malaria are routinely reported via local phy-

sicians and diagnostic laboratories. For each case that had been

notified, an epidemiological investigation was performed by an

experienced public health nurse who verified the case and gath-

ered details regarding demographic data, date of onset andsymptoms of the disease, hospitalization, prophylactic use, and

area in which the infection was acquired.

Use of prophylaxis was defined as complete, when the

patient completed the course of mefloquine or doxycycline for

1 month after return from an area with chloroquine-resistant

malaria [5]; or partial, when the patient did not complete

the course or took inadequate prophylaxis (such as daraprim,

maloprim, or chloroquine with/without proguanil) to an area

with chloroquine-resistant malaria. The outcome of the disease

was defined as severe, according to the criteria of the World

Health Organization [6], or nonsevere.

The data were analyzed using the SAS program, version 6.12(SAS). Comparison of the proportion of severe cases of malaria

between categories of demographic and clinical characteristics

was performed using Fishers exact test. Univariate ORs and 95%

CIs for developing severe malaria were estimated for patients

who were !40 years of age compared with patients who were

40 years of age. These ORs were calculated separately for the

overall study group as well as for the nonprophylactic subgroup.

The relationship between age and prophylactic use (3 ordered

categories) was tested using the Wilcoxon rank sum test.

Results. From 1994 through 1999, a total of 387 cases of

malaria were reported to the Israel Ministry of Health. Of these

cases, 135 (113 in male patients and 22 in female patients) metthe criteria of P. falciparum malaria infection in nonimmune

patients (i.e., excluding immigrants and foreign visitors from

countries where malaria is endemic). The number of patients

with cases per year ranged from 13 to 32, with no specific trend

by time.

Table 1 presents certain demographic characteristics as well

as acquisition areas and malaria prophylaxis used by the study

population. Overall, 13 patients (9.6%) had cases that were


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BRIEF REPORTS CID 2001:33 (15 November) 1775

Table 1. Characteristics of all cases of Plasmodium falciparum

malaria in 19941999, by severity.

Characteristic

No. (%) of

subjects with

OR (95% CI)

Nonsevere

disease

(n p 122)

Severe

disease

(n p 13)

Sex

Female 20 (16.4) 2 (18.2)

Male 102 (83.6) 11 (81.8) 0.93 (0.194.51)

Age, years

!40 80 (65.6) 4 (30.7) 4.29 (1.2514.74)

40 42 (34.4) 9 (69.3)

Acquisition area

Missing or unknown 4 (3.3)

Africa 106 (86.8) 13 (100)

Asiaa

12 (9.8)

Prophylaxis

Yes, complete 9 (7.4) 0 (0)

Partial 36 (29.5) 2 (15.4)

No 66 (54.1) 11 (84.6) 0.27 (0.061.26)

Missing 11 (9.0)

Age in the subgroup of

patients without

prophylaxis, years

!40 37 (56.1) 3 (27.3) 3.4 (0.8313.98)

40 29 (43.9) 8 (72.7)

a

Pp .608; determined by means of Fishers exact test.

Table 2. Association between prophylaxis

use and age among the study groups.

Prophylaxis

No. (%) ofsubjects aged

Total!40 years 40 years

None 40 (51.95) 37 (78.72) 77

Partial 29 (37.66) 9 (19.15) 38

Full 8 (10.39) 1 (2.13) 9

Total 77 (100) 47 (100) 124

NOTE. Information regarding use of prophylaxis

was not available for 11 patients; Pp .0023

compatible with the criteria of severe disease. Features of severe

disease were cerebral malaria (5 cases), acute respiratory distresssyndrome (5 cases), acute renal failure (4 cases), and hepatitis

(2 cases).

Age was significantly associated with the risk for developing

severe disease: only 4 (5%) of the 84 patients who were !40

years of age contracted severe disease, compared with 9 (18%)

of the 51 patients who were 40 years of age (OR, 4.29; 95%

CI, 1.2514.74). In the same context, the mean age ( SD) of

the patients was years for patients with mild cases and35 12

years for patients with severe cases ( ). All 343 17 Pp .035

deaths occurred in patients who were 150 years of age (51, 55,

and 63 years of age). There was no relationship between patient

sex and severity of disease (10% of the patients with severe

disease were male and 9% were female). Most patients

(90.8%)and all patients with severe caseshad been infected

in Africa.

Only 9 patients had fully complied with recommendations

for prophylaxis. Age was inversely related to prophylactic use;

78.7% of the patients who were 40 years of age took no

prophylaxis, compared with 51.9% of the younger patients

( ; table 2).Pp .002

None of the patients who took full prophylaxis developed

severe disease, as compared with 5.3% in the partial-prophylaxis

group and 14% in the group who took no prophylaxis. These

facts indicate a trend of negative association between prophy-

laxis use and severity (without being statistically significant;

table 1).

The positive correlation between age and disease severity

seemed to be unrelated to prophylaxis, because there was a 3.4-fold risk for developing severe disease among people 40 years

of age when compared with the patients who were !40 years

of age, even among those who had not received any prophy-

lactic treatment (95% CI, 0.8313.98; table 1).

The 13 patients with severe cases were otherwise healthy, and

only 2 had a concomitant ischemic heart disease that was stable.

Three patients died (case fatality rate, 2.2% [3 of 135]): 2 pa-

tients had no underlying diseases, and the third had undergone

a coronary bypass 4 years prior to admission. The latter pa-

tients medical condition was excellent, which had allowed him

to travel frequently without any limitations.

Discussion. The increasing number of persons who travelto malarial areas is increasing the rate of imported malaria,

which has resulted in severe and fatal outcomes of a preventable

and treatable disease. The major finding of our study was the

positive association of malaria severity and age. In our nation-

wide analysis of P. falciparum malaria in nonimmune, Israeli

patients, we found a significantly higher rate of severe disease

and mortality among those patients who were 40 years of

age. Svenson et al. [3] studied imported malaria cases in Can-

ada; 182 of the patients in that study were infected with P.

falciparum. Of these patients, 13 were defined as having severe

malaria. Comparing the groups with severe and nonsevere dis-

ease, they found that age was not a significant contributing

factor to severity. Other studies, however, support our findings.

Baird et al. [7] investigated a transmigrant population in Irian

Jaya, Indonesia. Most of these nonimmune subjects were moved

to new villages in a malarious area. Mortality from malaria was

highest in the youngest (!2 years) and oldest age groups (140

years), 2.2% and 2.5%, respectively, compared with 0%0.9%

for patients who were 240 years of age.


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1776 CID 2001:33 (15 November) BRIEF REPORTS

Table 3. Age-related mortality among travelers with Plasmodium falciparum malaria.

Study country (authors [reference])

No. cases/total no. of subjects (%)

OR (95% CI)Overall

Patients aged

!40 years

Patients aged

40 years

United States (Greenberg et al. [4]) 66/1760 (3.8) 18/1041 (1.7) 47/671 (7) 4.28 (2.467.44)

Italy (Callieri et al. [8]) 3/194 (1.5) 1/116 (0.8) 2/75 (2.6) 3.15 (0.2835.37)

I ta ly ( Sa ba tinelli et a l. [9]) 22/998 (2.3) 6/ 482 (1.2) 17/473 (3.6) 2.96 ( 1. 167.57)

I ndonesia ( Baird et al. [7]) 8/1059 (0.8) 6/979 (0. 6) 2/80 (2.5) 4.16 (0.8320. 95)

Israel (present study) 3/135 (2.2) 0/84 (0) 3/51 (5.8) (2.47)

Overall 102/4146 (2.5) 31/2702 (1.1) 71/1350 (5.3) 3.97 (2.626.02)a

a

Common ORs and 95% CIs were computed using the Cochran-Mantel-Haenszel method (method-analysis over the 5

studies).

Greenberg and Lobel [4] analyzed 68 patients who died of

imported P. falciparum malaria in 19591987 in the United

States. A breakdown of the study population by age groups

showed that there was an increment in mortality by age: in the

019-, 2039-, 4069-, and 7079-year-old age groups, the case

fatality rates were 0.4%, 2.2%, 5.8%, and 30.3%, respectively.

Two Italian studies showed similar results. Calleri et al. [8]

studied disease severity in 194 cases that were due to P. falci-parum, 9% of which fulfilled the criteria of severe malaria. The

number of severe cases increased with age as follows: 3.2% of

cases in patients who were !30 years of age; 5.3%, for patients

3039 years of age; 9.8%, for patients 4049 years of age; and

23.5%, for patients 50 years of age. Sabatinelli et al. [9], who

studied mortality in malaria patients, showed a 2.3% case fa-

tality rate in patients with malaria due to P. falciparum, with

increment in mortality by age. There were no deaths in this

series among those patients who were !20 years of age; the

mortality rate was 0.5% in patients 2130 years of age; 2.3%,

in patients 3140 years of age; 1.7%, in patients 4150 years

of age; and 5.4%, in patients 51 years of age. All of thesestudies included a mixed population of nonimmune travelers

and immigrants, and all examined different end points (either

severity or mortality of malaria). Our study is based on a na-

tionwide cohort, focusing only on a uniform group of non-

immune travelers. Our results demonstrate that age (40 years)

is the most important risk factor for predicting severe malaria,

with OR of 4.3; the results are similar to those of Calleri et al.

[8], who calculated an OR of 5.1. In table 3, we summarize

the data from the aforementioned reports regarding malaria

mortality, and we show that, in 5 studies with a total of 4146

patients who had malaria due to P. falciparum, the pattern is

similar (i.e., a case fatality rate of 1.1% among the patients who

were !40 years of age, compared with 5.3% in patients who

were 40 years of age, which yields an OR of 3.97).

Patient sex as a risk factor for severe malaria has conflicting

results. Svenson et al. [3] reported that the risk for disease

severity was higher in female patients, and Sabatinelli et al. [9]

reported that female patients were at a higher risk for mortality;

however, Greenberg and Lobel [4] and Calleri et al. [8] were

unable to show that patient sex was a risk factor. Our data are

in accordance with the latter studies (table 1).

The vast majority of the patients in our study contracted the

disease in Africa (mostly in Kenya and Ghana), and, in parallel,

all severe cases of malaria were imported from Africa. Because

there were a small number of cases that were imported fromAsia (12 [8.8%] of 135 patients), we were prevented from any

statistical calculations for the risk of severe disease by acqui-

sition area. Taking prophylaxis (even if only partial) seems to

have a protective influence against developing severe malaria

in patients who took prophylaxis at the time that they acquired

malaria, although it did not reach the level of statistical sig-

nificance (table 1).

The reason for the increased vulnerability at the age of40

years is not clear. One explanation may be the underlying med-

ical conditions of the aged patients. Our findings could not

support such a theory, because most of the patients in our

study with severe malaria did not have any known medicalproblems (only 2 patients had coronary artery disease, and they

were in stable condition and had excellent functional capacity).

Baird et al. [8] hypothesized that different immune responses

that are related to age may be responsible for the different

outcomes. According to Clark [10], the susceptibility of the

aged population to the negative effect of cytokines excreted

during the disease may be higher. In fact, with regard to other

infectious diseases, such as hepatitis A, there has also been

shown to be an association between an age of 140 years of age

and severe morbidity and high mortality: the mortality rate is

2.5% for patients who are 140 years of age, compared with a

rate of!0.1% among younger patients [11].

We unexpectedly found that patients aged 40 years used

prophylaxis less than did younger patients (79% of the elderly

patients did not take any prophylaxis, compared with 52% of

the younger patients). Complete prophylaxis was taken by only

2% of the older patients, whereas 10% of the younger patients


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BRIEF REPORTS CID 2001:33 (15 November) 1777

took complete prophylaxis ( ; table 2). Moreover, whenPp .002

we examined the age distribution of travelers in 3 large travel

clinics in Israel, we found that, among the 15,720 travelers who

visited the clinics for pretravel consultation during the study

period, 77% were !40 years of age and only 23% were 40

years of age; however, among the patients with malaria, the

percentage of those who were 40 years of age and who pre-

sented to the travel clinics reached 38% ( ). The find-Pp .0001ing that the older patients with malaria tended to use less

malaria prophylaxis may not represent the entire population

of travelers, but, if so, it may explain the higher attack rate in

this population.

These findings should lead clinicians to provide travelers aged

40 years with strict instructions for prophylaxis of malaria,

apply the prophylaxis promptly, and vigorously treat patients

when they show the first clinical signs of malaria.

Acknowledgments

We would like to thank Dr. P. Slater and his staff from the

Department of Epidemiology, Israel Ministry of Health, Jeru-

salem, for their assistance in gathering the information.

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