Download impairment of host immune response against strongyloides

Am. J. Trop. Med. Hyg., 74(2), 2006, pp. 246–249
Copyright © 2006 by The American Society of Tropical Medicine and Hygiene
IMPAIRMENT OF HOST IMMUNE RESPONSE AGAINST STRONGYLOIDES
STERCORALIS BY HUMAN T CELL LYMPHOTROPIC VIRUS TYPE 1 INFECTION
TETSUO HIRATA,* NOBUFUMI UCHIMA, KAZUTO KISHIMOTO, OSAMU ZAHA, NAGISA KINJO,
AKIRA HOKAMA, HIROSHI SAKUGAWA, FUKUNORI KINJO, AND JIRO FUJITA
Control and Prevention of Infectious Diseases, Department of Medicine and Therapeutics, Faculty of Medicine, University of the
Ryukyus, Okinawa, Japan; Department of Endoscopy and Department of Blood Transfusion Medicine, Ryukyu University Hospital,
Okinawa, Japan; Department of Internal Medicine, Nakagami Hospital, Okinawa, Japan
Abstract. A large-scale study was undertaken to clarify the prevalence rate of strongyloidiasis in Okinawa, Japan and
to evaluate the relationship between strongyloidiasis and infection with human T cell lymphotropic virus type 1 (HTLV1). The prevalence rate of Strongyloides stercoralis and HTLV-1 infection were 6.3% and 14.0%, respectively. Among
2,185 patients more than 50 years of age, the rate of S. stercoralis infection was significantly higher in patients with
HTLV-1 infection compared with patients without HTLV-1 infection. In 252 patients treated with ivermectin, serum IgE
levels and peripheral eosinophil counts were significantly lower in HTLV-1 co-infected patients compared with patients
without HTLV-1 infection. In addition, the anthelmintic effect was significantly lower in patients with HTLV-1 infection
compared with patients without HTLV-1 infection. Our prospective study demonstrated a prevalence rate for strongyloidiasis and HTLV-1 infections, and clearly demonstrated that co-infection with HTLV-1 impaired the immune response against S. stercoralis.
INTRODUCTION
Patients for assessment of the therapeutic effect of ivermectin. These patients had mild-to-moderate strongyloidiasis
for a period 11 years from 1990 to 2001. Before entry to this
study, each patient was informed of the orphan-drug study, its
purpose, and potential side effects. The study included 252
patients with strongyloidiasis who were treated with ivermectin (administered orally at a dose of 100 ␮g/kg, and the same
dose was repeated two weeks later).
Assays to detect HTLV-1 infection and S. stercoralis infection. Serum antibody to HTLV-1 was prospectively measured
in all patients by the gelatin particle agglutination method,11
and infection of S. stercoralis was prospectively diagnosed
using the agar plate culture method.12 Written informed consent for examination was obtained from all patients. In patients where the therapeutic effect of ivermectin was assessed,
total serum IgE levels were determined by latex nephelometry and peripheral eosinophils were counted by May-Giemsa
staining.
Definition of the effect of anthelmintic treatment. The effect of anthelmintic treatment was assessed once 1–4 weeks
after the administration of ivermectin and a second time 12
months after the initial treatment. In the assessment of the
anthelmintic effect, as tested by the agar plate culture
method, patients whose stool was negative for S. stercoralis at
12 months after the initial treatment were considered cured.
Statistical analysis. The chi-square test was used to assess
differences between sex and between HTLV-1 positive and
negative patients. The Mann-Whitney U test was used to
compare serum IgE levels and peripheral eosinophil counts
between HTLV-1-positive patients and HTLV-1-negative patients.
Strongyloidiasis is widely distributed in tropical and subtropical areas. In Japan, Okinawa Prefecture, which is in the
subtropics, has is an area endemic for Strongyloides stercoralis
infection. In addition, Okinawa Prefecture has a high infection rate of human T cell lymphotropic virus type 1 (HTLV-1).
A close relationship between strongyloidiasis and HTLV-1
has been reported in disease-endemic areas.1–3 In addition, a
high prevalence rate of infection with S. stercoralis and a high
rate of therapeutic failure have been noted in HTLV-1 carriers.4–6 Furthermore, severe forms of strongyloidiasis have
been documented in patients with HTLV-1 infection.7,8 These
reports have indicated that HTLV-1 has strong immunologic
implications in patients with S. stercoralis infection. It has also
been reported that Th2 type of immune response is predominant in S. stercoralis infection and that serum IgE levels are
low in patients coinfected with S. stercoralis and HTLV-1.9,10
However, there have been few prospective studies evaluating the relationship between strongyloidiasis and HTLV-1
infections. With this background, we have conducted a prospective inpatient survey to examine the prevalence rate of
strongyloidiasis and HTLV-1 infection, and to evaluate the
relationship between these infections. In addition, we also
analyzed serum IgE levels and peripheral eosinophil counts to
evaluate immune response in patients with strongyloidiasis
who were treated with ivermectin.
SUBJECTS, MATERIALS, AND METHODS
Patients for evaluation of prevalence of S. stercoralis infection and HTLV-1 infection. The present study included
3,360 patients who were admitted to the First Department of
Internal Medicine, Ryukyu University Hospital, Okinawa, Japan, between 1991 and 2004.
RESULTS
Prevalence of S. stercoralis infection and HTLV-1 infection. The study population was composed of 2,000 males and
1,360 females with a mean ± SD age of 54.9 ± 17.5 years. More
than 95% of infected patients with S. stercoralis were more
than 50 years of age. The total prevalence rate of S. stercoralis
infection was 6.3% (213 of 3,360). The prevalence rate of S.
stercoralis infection in males and females was 7.8% (155 of
* Address correspondence to Tetsuo Hirata, Control and Prevention
of Infectious Diseases, Department of Medicine and Therapeutics,
Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. E-mail: [email protected]
.ac.jp
246
247
HTLV-1-IMPAIRED IMMUNE RESPONSE TO STRONGYLOIDES
TABLE 1
Prevalence of Strongyloides stercoralis infection
No. of S. stercoralis-positive patients/no. of tested patients (%)
Age, years
Male
Female
Total
0–19
20–29
30–39
40–49
50–59
60–69
70–79
ⱖ 80
Total
0/46 (0.0)
0/172 (0.0)
1/202 (0.5)
11/277 (4.0)
22/354 (6.2)
69/500 (13.8)
42/338 (12.4)
10/111 (9.0)
155/2000 (7.8)*
0/37 (0.0)
0/128 (0.0)
0/123 (0.0)
1/190 (0.5)
14/273 (5.1)
15/325 (4.6)
21/218 (9.6)
7/66 (10.6)
58/1360 (4.3)
0/83 (0.0)
0/300 (0.0)
1/325 (0.3)
12/467 (2.6)
36/627 (5.7)
84/825 (10.2)
63/556 (11.3)
17/177 (9.6)
213/3360 (6.3)
TABLE 3
Relationship between human T cell lymphotropic virus type 1
(HTLV-1) infection and rate of Strongyloides stercoralis infection
in patients more than 50 years old
No. of S. stercoralis-positive patients/no. of subjects (%)
HTLV-1
Male
Female
Total
Positive
Negative
Total
36/211 (17.1)*
107/1092 (9.8)
143/1303 (11.0)
28/182 (15.4)†
29/700 (4.1)
57/882 (6.5)
64/393 (16.3)‡
136/1792 (7.6)
200/2185 (9.2)
* P ⳱ 0.002 for HTLV-1-positive patients vs. negative patients by chi-square analysis.
† P < 0.001 for HTLV-1-positive patients vs. negative patients by chi-square analysis.
‡ P < 0.001 for HTLV-1 positive patients vs. negative patients by chi-square analysis.
* P < 0.001 for male vs. female by chi-square analysis.
2,000) and 4.3% (58 of 1,360), respectively. The prevalence
rate in males was significantly higher compared with the
prevalence rate in females (P < 0.0001) (Table 1). The prevalence rate of S. stercoralis infection gradually increased with
age (Table 1).
The total prevalence rate of HTLV-1 infection was 14.0%
(472 of 3,360). The prevalence rate of HTLV-1 infection in
males and in females was 12.8% (256 of 2,000) and 15.9%
(216 of 1,360), respectively. The prevalence rate in females
was significantly higher compared with males (P ⳱ 0.012)
(Table 2). The prevalence rate of HTLV-1 infection gradually
increased with age (Table 2).
To evaluate the relationship between HTLV-1 infection
and S. stercoralis infection, the prevalence rate of S. stercoralis
infection was compared in HTLV-1-positive patients (more
than 50 years of age) and in HTLV-1-negative patients (more
than 50 years of age). The prevalence rate of S. stercoralis
infection was significantly higher in patients with HTLV-1
infection (16.3%) compared with patients without HTLV-1
infection (7.6%) (P < 0.0001) (Table 3). In addition, the
prevalence rate of HTLV-1 infection was significantly higher
in patients with S. stercoralis infection (32.0%) compared with
patients without S. stercoralis infection (16.6%) (P < 0.0001)
(Table 4). The differences were more pronounced in female
patients than in male patients (Table 4).
Assessment of the therapeutic effect of ivermectin. The
eradication rate of S. stercoralis by ivermectin was significantly lower in patients with HTLV-1 infection (50.0%) compared with patients without HTLV-1 infection (92.7%) (P <
0.0001) (Table 5).
TABLE 2
Prevalence of human T cell lymphotropic virus type 1
(HTLV-1) infection
No. of HTLV-1-positive patients/no. of tested patients (%)
Age, years
Male
Female
Total
0–19
20–29
30–39
40–49
50–59
60–69
70–79
ⱖ 80
Total
1/46 (2.2)
3/172 (1.7)
14/202 (6.9)
27/277 (9.7)
59/354 (16.7)
68/500 (13.6)
64/338 (18.9)
20/111 (18.0)
256/2000 (12.8)
1/37 (2.7)
6/128 (4.7)
11/123 (8.9)
16/190 (8.4)
43/273 (15.8)
61/325 (18.8)
61/218 (28.0)
17/66 (25.8)
216/1360 (15.9)*
2/83 (2.4)
9/300 (3.0)
25/325 (7.7)
43/467 (9.2)
102/627 (16.3)
129/825 (15.6)
125/556 (22.5)
37/177 (20.9)
472/3360 (14.0)
* P ⳱ 0.012 for female vs. male by chi-square analysis.
Serum IgE levels were significantly lower in patients with
HTLV-1 infection (mean ± SD ⳱ 587.5 ± 442.6 IU/mL) compared with patients without HTLV-1 infection (1,116.2 ±
836.5 IU/mL) (P < 0.0001). In addition, peripheral eosinophil
counts were also significantly lower in patients with HTLV-1
infection (381.6 ± 222.7/mm3) compared with patients without HTLV-1 infection (593.3 ± 891.0/mm3) (P ⳱ 0.0035)
(Table 6).
DISCUSSION
Strongyloides stercoralis lives in warm and wet soil. Filariform larvae infect humans through the skin of bare feet. After
infection, larvae migrate to the duodenum and grow into mature females. Rhabditiform larvae hatched from eggs are
ejected from the host. However, some develop into filariform
larvae and reinfect through the colon or anal skin (autoinfection). Therefore, once infected, the carrier state of S. stercoralis lasts for a long time.
In the present study, the infection rate of S. stercoralis was
6.3% and most patients were more than 50 years of age. The
increased rate of strongyloidiasis in patients more than 50
years of age was probably due to the cumulative risk of infection over time. The prevalence of S. stercoralis infection
was significantly higher in males compared with females. This
result was similar to those of previous reports.13,14 Hayashi
and others reported that in the Yaeyama District in Okinawa,
Japan, residents worked barefoot in rice paddies and used
human excreta as fertilizer until 1965.13 In addition, since
male farmers were primarily responsible for distributing human feces in fields, it was assumed that males were more
readily exposed to S. stercoralis.13
Human T cell lymphotropic virus type 1 is transmitted by
three routes: the first is vertical (in the breast milk or transplacental), the second is horizontal (sexual), and the third is
TABLE 4
Relationship between rate of Strongyloides stercoralis infection and
rate of human T cell lymphotropic virus type 1(HTLV-1) infection
in patients more than 50 years old
No. of HTLV-1-positive/no. of subjects (%)
S. stercoralis
Male
Female
Total
Positive
Negative
Total
36/143 (25.2)*
175/1160 (15.1)
211/1303 (16.2)
28/57 (49.1)†
154/825 (18.7)
182/882 (20.6)
64/200 (32.0)‡
329/1985 (16.6)
393/2185 (18.0)
* P ⳱ 0.002 for S. stercoralis-positive patients vs. negative patients by chi-square analysis.
† P < 0.0001 for S. stercoralis-positive patients vs. negative patients by chi-square analysis.
‡ P < 0.0001 for S. stercoralis-positive patients vs. negative patients by chi-square analysis.
248
HIRATA AND OTHERS
TABLE 5
Comparison of the anthelmintic effect of ivermectin between patients
with human T cell lymphotropic virus type 1 (HTLV-1) infection
and patients without HTLV-1 infection
HTLV-1
No. cured/no. of subjects (%)
Positive
Negative
Total
28/56 (50.0)*
89/96 (92.7)
117/152 (77.0)
* P < 0.0001 for HTLV-1 negative patients vs. positive patients by chi-square analysis.
parenteral (blood transfusion or intravenous drug use).15 In
accordance with a previous report,13 the prevalence of
HTLV-1 infection was significantly higher in females compared with males, suggesting that horizontal (sexual) transmission played a role in HTLV-1 infection. As demonstrated
in the present study, the low prevalence rate of HTLV-1 infection in younger patients might be due to improved public
health, as well as a better knowledge of routes of HTLV-1
transmission. In the present study, serum antibody to
HTLV-1 was measured by the gelatin particle agglutination
method. It has been reported that the specificity and sensitivity of the gelatin particle agglutination test are higher compared with those of the particle agglutination test and indirect
immunofluorescence assay.11
The present prospective study clearly demonstrates that
there was a strong relationship between HTLV-1 infection
and S. stercoralis infection. The prevalence rate of S. stercoralis infection was significantly higher in patients with HTLV-1
infection compared with patients without HTLV-1 infection.
Previous studies have demonstrated similar results in Okinawa, Japan.1,13
In the present study, the eradication rate with ivermectin
administrated at a dose of 100 ␮g/kg was significantly lower in
patients with HTLV-1 infection compared with patients without HTLV-1 infection. At the beginning of this study, we
decided to use a dose of 100 ␮g/kg per dose instead of 200
␮g/kg to reduce the occurrence of any side effects of related
to ivermectin. In addition, because it has been suggested that
ivermectin is ineffective against larvae and eggs within human
tissues, and because it takes two weeks from the time of a
percutaneous infection of S. stercoralis until S. stercoralis is
discharged into the feces, we administered ivermectin again
two weeks later. However, as demonstrated in the present
study, the anthelmintic rate of ivermectin at a dose of 100
␮g/kg was low, especially in patients with HTLV-1 infection.
Therefore, since 2002, we have increased the single dose
amount of ivermectin from 100 ␮g/kg per dose to 200 ␮g/kg
per dose. In accordance with the present study, higher rates of
therapeutic failure with ivermectin or thiabendazole against
S. stercoralis in patients with HTLV-1 infection have been
reported.4,16
TABLE 6
Comparison of serum IgE levels and eosionophils counts between
human T cell lymphotropic virus type 1 (HTLV-1)-positive patients
and HTLV-1-negative patients*
HTLV-1
Serum IgE (IU/mL)
Eosinophils (/mm3)
Positive
Negative
587.5 ± 442.6†
1,116.2 ± 836.5
381.6 ± 222.7‡
593.3 ± 891.0
* Values are the mean ± SD.
† P < 0.0001 for HTLV-1-positive vs. negative by the Mann-Whitney U test.
‡ P ⳱ 0.0035 for HTLV-1-positive vs. negative by the Mann-Whitney U test.
The development of strongyloidiasis in HTLV-1-infected
individuals is due to two factors: impairment of the immune
mechanism against S. stercoralis and decreased efficacy of
anti-helminth drugs in patients co-infected with HTLV-1 and
helminthes. The reasons for the decreased efficacy of antiheminth drugs in patients infected with both S. stercoralis and
HTLV-1 are not clear, but because the immune mechanisms
against S. stercoralis are decreased in patients infected with
HTLV-1, it is likely that the efficacy of the drugs also depends
on intact immune responses.3
In S. stercoralis infection, a Th2 type immune response is
predominant. However, patients infected with HTLV-1 have
spontaneous T lymphocyte proliferation and infected T lymphocytes produce high levels of interferon-␥, which are associated with the Th1 type of immune response. In contrast,
HTLV-1-infected T lymphocytes produce low levels of interleukin-4, as well as interleukin-5, which play an important
role in the Th2 type immune response.10,17 However, as demonstrated in the present study, patients co-infected with
HTLV-1 had significantly lower levels of serum IgE and peripheral eosinophil counts compared with patients without
HTLV-1 infection. In accordance with this evidence, in the
present study, the prevalence rate of S. stercoralis infection
and the rate of therapeutic failure were high in patients with
HTLV-1 infection compared with patients without HTLV-1
infection. Since the Th2 type immune response is necessary
for defense against helminthes, and eosionophils and IgE
have important roles against helminthes,9,18 these results suggest that co-infection with HTLV-1 may impair the Th2 type
of immune response in patients infected with S. stercoralis.
In conclusion, our prospective study clearly demonstrates
the relationship between S. stercoralis infection and HTLV-1
infection. Since impairment of the immune response to S.
stercoralis was evident in patients co-infected with HTLV-1,
new strategies to eradicate S. stercoralis should be established
in future studies.
Received August 4, 2005. Accepted for publication October 9, 2005.
Authors’ addresses: Tetsuo Hirata, Nobufumi Uchima, Akira
Hokama, and Jiro Fujita, Control and Prevention of Infectious Diseases, Department of Medicine and Therapeutics, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa
903-0215, Japan, Telephone: 81-98-895-1144, Fax: 81-98-895-1414,
E-mails: [email protected], [email protected],
[email protected], and [email protected]. Kazuto Kishimoto, Nagisa Kinjo, and Fukunori Kinjo, Department of
Endoscopy, Ryukyu University Hospital, 207 Uehara, Nishihara,
Okinawa 903-0215, Japan, Telephone: 81-98-895-1144, Fax: 81-98895-1414, E-mails: [email protected], [email protected]
.ac.jp and [email protected]. Osamu Zaha, Department
of Internal Medicine, Nakagami Hospital, 6-25-5 Chibana, Okinawa
city, Okinawa, Japan, Telephone: 81-98-939-1300, Fax: 81-98-9378699, E-mail: [email protected]. Hiroshi Sakugawa, Department of Blood transfusion Medicine, Ryukyu University Hospital,
207 Uehara, Nishihara, Okinawa 903-0215, Japan, Telephone: 81-98895-1144, Fax: 81-98-895-1414, E-mail: [email protected].
Reprint requests: Tetsuo Hirata, Control and Prevention of Infectious Diseases, Department of Medicine and Therapeutics, Faculty of
Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan, E-mail: [email protected]
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