Download Infectious Complications of Human T Cell Leukemia/Lymphoma

138
Infectious Complications of Human T Cell Leukemia/Lymphoma Virus Type I
Infection
Bryan J. Marsh
From the Infectious Disease Section, Dartmouth-Hitchcock Medical
Center, Lebanon, New Hampshire
Infection with human T cell leukemiallymphoma virus type I (HTLV-I) has been etiologically
associated with two diseases: adult T cell leukemia and HTLV-I-associated myelopathy/tropical
spastic paraparesis. Increasing evidence suggests that HTLV-I infection may be associated with
immunosuppression and, as a consequence, affect the risk and expression of several other infectious
diseases, of which the best studied are strongyloidiasis, tuberculosis, and leprosy. In strongyloidiasis,
coinfection with HTLV-I appears to result in a higher rate of chronic carriage, an increased parasite
load, and a risk of more severeinfection. In tuberculosis, a decreasein delayed-typehypersensitivity
to Mycobacterium tuberculosis has beenestablished, but whether this decreaseis clinicallysignificant
has yet to be determined. In leprosy, an increased risk of disease is suggested, but the published
studies are all too poorly controlled to draw definite conclusions.
The spectrum of immune dysregulation produced by viral
infections is wide, spanning the transient and relatively benign
leukopenia associated with many acute viral infections to the
progressive CD4 lymphocytopenia and profound immunodeficiency associated with chronic infection with HIV. Despite
our rapidly growing understanding of many aspects of these
infections, the immunologic consequences of chronic infection
by viruses other than HIV remain poorly understood. Viruses of
obvious concern in this regard include human T cell leukemia!
lymphoma virus types I and II (HTLV-I and HTLV-II). Both
viruses produce lifelong latent infection, and both infect T
lymphocytes (HTLV-I, primarily CD4+ cells; HTLV-II, primarily CD8+ cells).
HTLV-I is now known to be etiologically associated with
at least two diseases, and there is extensive and impressive
literature on the in vitro immune modulation produced by the
virus. HTLV-II on the other hand remains an orphan virus,
without any confirmed disease association. This review focuses
on the clinical and epidemiologic studies that pertain to a possible immune perturbation produced by latent infection with
HTLV-I and its consequent effects on the risks of coinfection
with other infectious agents.
Much has been learned about the virology, epidemiology,
and natural history of HTLV-I since its discovery in the late
1970s [1, 2]. These subjects have been reviewed recently, and
only relevant aspects will be detailed here [3]. HTLV-I and
HTLV-II are the only members of the Oncovirnae subfamily
of the family Retroviridae known to infect humans. HTLV-I
primarily infects CD4+ cells, with subsequent integration of
the viral genome into the genome of the host's CD4+ cells.
Received 11 October 1995; revised 21 February 1996.
Reprints or correspondence: Dr. Bryan J. Marsh, Infectious Disease Section,
Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756.
Clinical Infectious Diseases
1996;23:138-45
© 1996 by The University of Chicago. All rights reserved.
1058--4838/96/2301-0019$02.00
While HTLV-I infection is in this latent state, which can
last indefinitely, it is able to avoid immunologic surveillance
despite the fact that the viral genome can be found polyclonally
integrated in up to 15% of circulating T lymphocytes [4-6].
The only proven modes of transmission of HTLV-I are sexual,
parenteral (via transfusion and needle sharing), and vertical
(congenitally and via breast-feeding), but the possibility of
environmental and vector-borne transmission is still debated
[7-11].
HTLV-I is found worldwide, but the prevalence of HTLVI infection varies widely both over large geographic areas and
within areas of endemicity. The two areas with the highest
prevalence rates are the Caribbean basin (4%-9% [8]) and the
islands of southwestern Japan (37% [12]). One study of global
seroprevalence estimates that between 11 and 20 million people
are currently infected with HTLV-I [13].
In the United States, the combined prevalence rates of
HTLV-I and HTLV-II infections in >600,000 blood donors
was 0.05%; about 40% of these donors were infected with
HTLV-I, and the remainder were infected with HTLV-II [14].
The major risk factors for infection in the blood donor studies
in the United States were origin from an area of endemicity
and sexual intercourse with a partner from such an area [15].
Intravenous drug use has also been shown to be a significant
risk for infection with HTLV-I in the United States [16,17].
Diagnosis of infection with HTLV-I is usually serological
and is complicated by significant cross-reactivity with HTLVII [18]. Specific peptide tests and PCR now allow for accurate
distinction between the two viruses [19], but in clinical studies
performed before 1990, this distinction was not possible. Unless otherwise noted, the studies discussed below were all performed in areas with endemic HTLV-I but not HTLV-II.
Natural History
Infection with HTLV-I is persistent and lifelong. In a small
percentage of infected individuals, one of the noninfectious
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(July)
Infectious Complications of HTLV-I Infection
clinical sequelae subsequently develops, but most of these individuals are thought to remain asymptomatic. There are only two
diseases, adult T cell leukemia (ATL) and HTLV-I-associated
myelopathy/tropical spastic paraparesis (HAM/TSP), definitively associated with HTLV-I infection.
ATL
ATL is the most common major sequela of infection with
HTLV-I, and in areas of endemicity, it occurs in ~4% of
HTLV-I-infected individuals [20]. The median age of onset of
ATL in one study was 56 years [21], suggesting a period of
latent infection as long as several decades. This suggestion is
supported by a model for the risk of ATL that was based on
a combination of cross-sectional data and a case-control study
from Jamaica [20], and this model has led to the assumption
that most, if not all, cases of ATL develop in individuals infected with HTLV-I since birth [22].
ATL can present in one of several forms (which may be
stages in the natural history of ATL). Although there is significant geographic variation in the contribution of these forms to
the initial presentation, the most common presentation is acute
leukemia.
The most benign detectable form of ATL is an asymptomatic
preleukemic phase usually diagnosed incidentally when examination of a peripheral blood smear reveals abnormal lymphocytes with characteristic lobulated nuclei. About one-half of
patients with this preleukemic phase have spontaneous resolution, but the conditions ofthe other one-half eventually progress
to a symptomatic stage of disease [23].
Smoldering ATL is the most benign symptomatic form of
disease and is characterized by cutaneous but no visceral lesions, a normal peripheral blood leukocyte count, and a few
circulating leukemic cells. The development of chronic ATL
is marked by visceral involvement and is evidenced by lymphadenopathy, hepatosplenomegaly, and peripheral blood leukocytosis. Both of the relatively benign or early forms of symptomatic ATL can progress to acute ATL.
Acute ATL is a fulminant disease; the median life expectancy of individuals with acute ATL is 11 months. Patients with
acute ATL have cutaneous and visceral involvement, peripheral
blood leukocytosis, elevated levels of lactate dehydrogenase
and bilirubin, and often hypercalcemia. As recently reviewed
by Rhew et al. [24], ATL is associated with severe immunosuppression as evidenced by the susceptibility of these patients to
various opportunistic infections, including Pneumocystis carinii pneumonia, cryptococcal meningitis, candidal esophagitis,
and disseminated cytomegalovirus infection. Occasional longterm survival has been described, but the disease is usually
unresponsive to conventional chemotherapy. Recent reports of
immunotherapeutic trials allow for a degree of optimism [25].
HAM/TSP
The second of the two syndromes associated with chronic
infection with HTLV-I is HAM/TSP, also known as HTLV-I
139
myelopathy. This syndrome afflicts < 1% of individuals from
areas of endemicity who are infected with HTLV-I [26]. Patients are largely adults, although somewhat younger than those
who have ATL. On the basis of cases associated with blood
transfusion, a median latent period of infection as short as 3.3
years has been described [27], thus suggesting that most cases
occur in individuals who acquired HTLV-I infection as adults
rather than vertically.
The syndrome is one of progressive spastic paraparesis, predominantly of the lower extremities, and is associated with
hyperreflexia, sensory disturbances, and urinary incontinence
[28]. Cognitive function and cranial nerves are not affected.
The pathology is demyelination, primarily in the spinal cord.
Other Putative Disease Correlations
There have been many other noninfectious syndromes associated with latent HTLV-I infection, but none of these syndromes have been definitively linked to HTLV-I. Among the
more likely putative correlates are uveitis [29, 30], polymyositis [31], lymphocytic interstitial pneumonia [32], inflammatory arthritis [33-35], and mycosis fungoides [36-38].
Asymptomatic Infection
Most ('"'-'95%) individuals chronically infected with HTLV1have been thought to remain entirely asymptomatic. However,
a growing body of literature suggests that some or many of
these infected individuals may have a mild but clinically significant form of chronic immunosuppression.
Clinical Evidence for Immunosuppression in Chronic
HTL V-I Infection
The immunosuppression associated with ATL is well documented [39]. There is also now a considerable volume of in
vitro and clinical evidence suggesting a significant perturbation
of the immune function in individuals with asymptomatic
HTLV-I infection (table 1). Evidence includes an increased
risk of acute and chronic infection by several pathogens, an
increased rate of reactivation tuberculosis, case reports of opportunistic infections, and depressed cell-mediated immunity as
demonstrated by skin testing for delayed-type hypersensitivity
(DTH). The most consistent and convincing evidence involves
the interaction between HTLV-I infection and three infections-strongyloidiasis, tuberculosis, and leprosy (table 2).
Strongyloidiasis
Studies on the association between Strongyloides stercoralis
infection and HTLV-I infection have been conducted in both
Japan [40-43, 64, 65] and Jamaica [44-46, 55]. These studies
used serological and microbiological methods, which are not
directly comparable, to define S. stercoralis infection. Sero-
Marsh
140
Table 1. Clinical evidence that chronic HTLV-I infection is immunosuppressive.
Effect of chronic HTLV-I infection
Increased prevalence of
Strongyloidiasis
Leprosy
Chronic skin sores
Increased severity of
Strongyloidiasis
Norwegian scabies
Novel infection
Infective dermatitis
Opportunistic infections
Cryptococcosis
Pneumocystis carinii pneumonia
Kaposi's sarcoma
Depressed cell-mediated immunity
Anergy to PPD
NOTE.
[Reference(s)]
[40-46]
[47-49]
[50]
[44,51-55]
[56]
[57]
[58]
[59]
[60]
[61-63]
HTLV-I = human T cell leukemia/lymphoma virus type I.
prevalence studies determine the number of individuals who
were ever infected, and stool culture studies determine the
number of individuals who are currently infected.
If HTLV-I has an effect on the host's ability to clear infection
with Strongyloides rather than on the risk of acquiring infection,
one would expect equal seroprevalencesof antibodies to Strongyloides in HTLV-I-positive and HTLV-I-negative groups but a
higher prevalence of Strongyloides in stool from HTLV-I-positive
patients. In addition, the titers of antibody to Strongyloides in
patients coinfected with HTLV-I may steadily decline [51]. If this
is a common phenomenon in individuals infected with HTLV-I,
then a falsely low serological estimate of S. stercoralis infection
in HTLV-I-positive subjects might result. Therefore,studies based
on stool culture for S. stercoralis provide a better method for
detecting HTLV-I-induced immunosuppression than do studies
based on seroprevalence of S. stercoralis infection.
In Japan, several stool culture studies documented that the
risk of active infection with S. stercoralis is significantly higher
in subjects who are HTLV-I-positive than in subjects who are
HTLV-I-negative [40-43]. The studies were primarily from
areas where HTLV-I is endemic and examined results from
both HTLV-I serologies for subjects for whom stool cultures
were positive for Strongyloides and stool cultures for subjects
known to be HTLV-I-positive.
These studies usually found a relative risk of strongyloidiasis
of ......,3-4. The details of case and control selection were often
not presented, but the samples were large enough and the prevalence rates of HTLV-I infection were high enough that a significant association between HTLV-I infection and stool carriage of Strongyloides seems likely in Japan.
Two stool culture studies from Japan were unable to demonstrate an association between HTLV-I infection and S. stercoralis carriage [64, 65]; however, both studies have significant
limitations. Both studies used a highly sensitive technique for
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stool culture that does not distinguish minimal carriage from
more significant disease. In addition, one study [64] failed to
perform simultaneous HTLV-I serologies for cases and controls, failed to consider confounding variables that might affect
the epidemiology of either of these infections in two very
different locations, and compared populations by means of data
collected in two different studies.
In Jamaica, studies based on stool culture for S. stercoralis
also showed an association with HTLV-I [44, 45]. Terry et al.
[44] found that 12 (44%) of27 patients for whom stool cultures
were positive for strongyloidiasis were HTLV-I-positive, while
oof 13 controls (minor or no gastrointestinal disease) for whom
stool cultures were negative were HTLV-I-positive. Likewise,
in a survey of 67 persons, Robinson et al. [45] found that 67%
of patients for whom stool cultures were positive were HTLVI-positive, while only 15% of patients for whom stool cultures
were negative were HTLV-I-positive (P = .01).
A study in Jamaica that used seroprevalence as the definition
of infection with S. stercoralis failed to show an association
with HTLV-I infection [55]. This study of94 HTLV-I-positive
and 106 HTLV-I-negative healthy food handlers found no difference in Strongyloides seropositivity between the two groups
(29% vs. 25%, respectively; P = .36).
The discrepancy between serological and stool culture studies was addressed in an outpatient study from Jamaica [46].
Serological studies for HTLV-I and Strongyloides were performed on nine patients with symptomatic strongyloidiasis for
whom stools were positive for Strongyloides and on 198
asymptomatic subjects who were from areas geographically
clustered around the areas where the initial cases were from.
Larvae were found in the stools of eight (4%) of the asymptomatic subjects (combined prevalence of stool carriage, 17 [8.2%]
of 207). The seroprevalence of strongyloides infection in the
combined sample of patients was 62 (30%) of 207. HTLV-I
positivity was found in 14 (22.6%) of 62 of the Strongyloidesseropositive subjects and nine (6.2%) of 145 of Strongyloidesseronegative subjects, while HTLV-I positivity was found in
10 (58.8%) of 17 subjects for whom stools were positive for
Strongyloides and 13 (6.8%) of 190 subjects for whom stools
were negative for Strongyloides.
The increased HTLV-I positivity in the Strongyloides-seropositive subjects was attributable to the high rate of HTLV-I
positivity in the symptomatic subjects for whom stools were
positive; therefore, this increased positivity reflects the bias
introduced by the inclusion of nine nonrandomly selected
symptomatic subjects into the study population and does not
represent a real association between HTLV-I infection and
seroprevalence of strongyloides infection. However, the increased HTLV-I positivity in the subjects for whom stools were
positive for Strongyloides could not be attributed solely to the
inclusion of the nine symptomatic subjects and thus appears
to represent a real association. Therefore, prior infection with
Strongyloides is not more common in HILV-I-positive subjects, but active infection is.
cm
1996;23
Infectious Complications of HTLV-I Infection
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141
Table 2. Evidence for an immunomodulatory effect ofHTLV-I infection on infection withand disease
produced by three human pathogens.
Immunomodulatory effect [reference(s)]
Pathogen, manifestation
Strongyloides stercoralis
Serological studies show no relationship between HTLV-I infection and risk of
infection with S. stercoralis [46, 55].
Most stool culture studies show a positive association between HTLV-I and
parasite load and HTLV-I and rate ofchronic carriage of S. stercoralis [4046]. Two negative stool culture studies have significant design limitations
[64, 65]. Disease may be more severe as suggested by several case reports
[44, 51-54] and by the observation that reports of S. stercoralis
hyperinfection are often from areas where HTLV-I is endemic [66]; however.
there are no controlled studies orcase series.
Infection
Disease
Mycobacterium tuberculosis
No pertinent studies have been reported.
The only study that has examined the effect ofHTLV-I infection on the risk of
tuberculosis failed to show a positive association but was inconclusive
(inadequate controls and only five subjects infected with HTLV-I) [67]. No
studies address a possible effect ofcoinfection with HTLV-Ion the severity
of tuberculosis.
Several studies demonstrate a significant suppression ofdelayed-type
hypersensitivity to PPD in subjects with HTLV-I infection [61-63].
Infection
Disease
Other
Mycobacterium leprae
No pertinent studies have been reported.
Three studies demonstrate a positive association between infection with HTLV-I
and the risk of leprosy [47-49]. The one negative study was inconclusive
(only three HTLV-I-infected subjects) [68]. No studies address an effect of
HTLV-I infection on the severity ofleprosy.
Infection
Disease
NOTE. HTLV-I
=
human T cell leukemia/lymphoma virus type I.
The clinical sequelae of coinfection with HTLV-I and
S. stercoralis have not been well defined. The Japanese prevalence studies all lack sufficient clinical data for determining if
strongyloidiasis is clinically distinct in HTLV-I-positive individuals. Case reports, however, suggested that coinfection with
these two pathogens might lead to more severe strongyloidiasis
[44,51-54]; these reports described HTLV-I-positive patients
with symptomatic, often severe, strongyloidiasis refractory to
usually effective therapy. In addition, Neva [66] noted that
cases of hyperinfection with S. stercoralis are often described
in patients from areas in which HTLV-I is endemic.
A partial explanation for the increased severity of strongyloidiasis in individuals coinfected with HTLV-I is offered by
Robinson et al. [45]. These authors noted markedly reduced
titers of total serum IgE in coinfected patients; Robinson et al.
suggested that, if the serum IgE levels correlated with intestinal
mucosal levels, this might' 'permit increased rates of autoinfection of the parasite and result in correspondingly greater worm
loads and patient morbidity."
If an association between HTLV-I infection and strongyloidiasis exists, an important question is whether the HTLV-Iinfected population is uniformly at risk or whether the risk
may be present just in specific subgroups. This issue was addressed by Nakada et al. [69] who examined 36 coinfected
patients in Japan who were receiving therapy for various condi-
tions. Fourteen (39%) of these subjects had monoclonal integration ofHTLV-I proviral DNA in peripheral blood lymphocytes,
7 (19%) had polyclonal integration, and 15 (42%) had undetectable proviral DNA. Monoclonal integration of viral DNA is
indicative of clonal expansion and is a necessary, although
probably not sufficient, step in the pathogenesis of ATL. There
was a trend, although not statistically significant, toward moresevere clinical strongyloidiasis in the group with monoclonal
integration of HTLV-I proviral DNA.
Since ATL develops in <4% of individuals infected with
HTLV-I [20], the study by Nakada et al. [69] suggests that a
disproportionate number of patients with strongyloidiasis may
have ATL. In addition, several of the case reports of severe
strongyloidiasis also mention eventual progression to ATL.
This progression implies either that S. stercoralis influences
the development of ATL or that S. stercoralis is a marker of
significant immune dysfunction in some patients infected with
HTLV-I. Thus, one subset of individuals at risk of strongyloidiasis may be patients with an early form of preleukemic ATL.
However, this association could explain only a small proportion of the patients with coinfection.
In summary, infection with HTLV-I does not appear to influence the risk of primary infection with S. stercoralis. However, it seems likely that coinfection with HTLV-I does alter
the host's immune response to S. stercoralis, resulting in a
142
Marsh
higher rate of chronic carriage, an increased parasite load, and
a risk of more severe infection.
Tuberculosis
The host's immune response to Mycobacterium tuberculosis
is critically dependent on T cell function. Because HTLV-I
causes chronic T cell infection, several studies have investigated the effect of HTLV-I infection on both infection and
disease due to M tuberculosis [61-63, 67].
Two lines of investigation have addressed the immunologic
effects of HTLV-I infection on the risk of tuberculosis. The
more extensive evidence concerns the effect of HTLV-I infection on DTH to PPD. Three studies from Japan demonstrated
a significant suppression ofDTH to PPD [61-63]. In the largest
and most recent study, PPD skin tests were performed on a
cohort of 528 subjects in a study of the natural history of
HTLV-I infection in Japan (the Miyazaki Cohort) [62]. The
subjects included 378 HTLV-I-negative subjects, 125 HTLVI-positive subjects without abnormal peripheral blood lymphocytes, and 25 HTLV-I-positive subjects with abnormal peripheral blood lymphocytes. The three groups were purportedly
demographically similar, although details, including those on
BCG vaccination, were not presented.
PPD reactions were evaluated on the basis of both erythema
and induration. The relative risk for a reduced PPD reaction
was 2.6 among seropositive subjects, which was a significant
difference that persisted after correction for the older age of
the seropositive group. No difference in risk was detected in
seropositive subgroups on the basis of the presence of abnormal
lymphocytes, antibody to tax, or detectable proviral DNA.
These results supported those from two earlier studies [61,
63]. The authors concluded that there is a clinically detectable
deficit in DTH to PPD in patients with asymptomatic HTLVI infection and that "sub-clinical immune suppression in
HTLV-I carriers is a process associated with carriers per se,
and not with increased viral replication or load."
A reduced response to PPD skin tests reflects an alteration
in immunologic function that could be associated with a reduction in the immune surveillance necessary to prevent reactivation of latent tuberculosis, but the extent of this effect has not
been adequately investigated.
Only one study has directly addressed this issue, but it was
conducted in an area with a low prevalence of infection with
HTLV-I. Kaplan et al. [67] selected 197 consecutive patients
in Senegal, West Africa, who were admitted to the hospital
with the diagnosis of pulmonary tuberculosis; they matched
these subjects by age, gender, and ethnic group to 197 controls
from a large study of HIV infection at another hospital. All
cases and controls were tested for antibodies to HTLV-I and
HIV. Three (1.5%) of the cases with tuberculosis were coinfected with HTLV-I vs. two (1.02%) ofthe controls. In contrast,
11 (5.6%) of the cases but only three (1.5%) of the controls
were coinfected with HIV (OR, 3.4). The authors concluded
em 1996;23
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that there was an association between HIV infection and active
tuberculosis but not between HTLV-I infection and active tuberculosis.
The conclusions of Kaplan et al. [67] need to be viewed
with skepticism for several reasons. First, controls were selected from a population potentially very distinct from the study
population. Second, because of the low prevalence of HTLVI infection, the study had power to detect only an odds ratio
for tuberculosis in patients infected with HTLV-I (4.2) that
was higher than that (3.4) for tuberculosis in patients infected
with HIV. Finally, an odds ratio of 3.4 for tuberculosis in
patients infected with HIV is significantly lower than odds
ratios reported in other studies [70- 76] and again raises concern about the comparability of the cases and controls.
Thus, an effect of HTLV-Ion DTH to M. tuberculosis has
been established, but whether this effect translates into an increased risk of reactivation tuberculosis has yet to be demonstrated. A case-control or a longitudinal study of a population
among whom the prevalence of both HTLV-I infection and
tuberculosis is high is needed to settle this question.
Leprosy
Leprosy is another mycobacterial disease that has been described with increased frequency in subjects coinfected with
HTLV-I. The first case report of coinfection with HTLV-I
and Mycobacterium leprae appeared in 1990 [77], and three
subsequent studies have examined the association between
these two infections [47-49]. In the first of two reports, Verdier
et al. [47] performed a serological survey of 3,177 subjects
from the Ivory Coast, West Africa. The prevalence rate of
HTLV-I infection was 3.5% but varied widely among subsets
of the study population, from 16.7% among a group of socioeconomically deprived prostitutes to <2% among pregnant
women from two of the surveyed areas. An association with
leprosy was suggested by the fact that one of the higher rates
of HTLV-I infection was detected among a population of persons with leprosy who were recruited from a single village.
In an attempt to better define the association between HTLVI infection and leprosy, Verdier et al. [48] subsequently performed serological studies on 1,493 patients with clinical leprosy and 1,866 controls (matched by gender and age, when
possible, and by region for three countries) from four West
African countries. The seroprevalence ofHTLV-I infection was
too low in two of the four countries (0 of 168 cases in Yemen
and 3 of 508 cases in Senegal) to determine a possible relationship with leprosy. In Congo and the Ivory Coast, however,
there were enough cases to document an increased risk of
HTLV-I infection in leprosy cases compared with controls
(5.6% vs. 1.9%, respectively, in Congo and 5.7% vs. 1.5%,
respectively, in the Ivory Coast).
In a smaller study from Zaire, Kashala et al. [49] performed
serologies for HTLV-I, HTLV-I1, and HIV type 1 on 57 inpatients with leprosy, 39 asymptomatic close contacts of these
ern 1996; 23 (July)
Infectious Complications of HTLV-I Infection
patients (among whom the rate of asymptomatic leprosy was
thought to be high), and 500 pregnant women from a prenatal
clinic 64 km from the leprosarium. Prevalence rates of HTLV1 infection were 8.8% among patients with leprosy, 12.8%
among contacts, and among pregnant women. The contrasting
seroprevalence rates of HIV type 1 infection were 3.5%, 0,
and 3.6%, respectively. The authors concluded that HTLV-I
infection but not HIV infection may be a risk factor for leprosy.
The conclusions of this study should not be considered definitive since the controls were not comparable with the cases.
The one contradictory study is a seroprevalence study of
250 Ethiopian patients with leprosy and 248 controls (mostly
dermatology patients without leprosy) [68]. This study failed
to show an association between HTLV-1infection and leprosy,
but there were only three HTLV-I-infected subjects in the entire
study.
In summary, two inadequately controlled studies showed an
association between HTLV-I infection and leprosy [47, 49].
This association suggests that individuals coinfected with
HTLV-I and M leprae may have clinical leprosy more readily
than those infected with M. leprae alone. An association between leprosy and HTLV-I infection might seem surprising
given the absence of an association between leprosy and HIV
infection, but because of the long latent period in leprosy, it
is possible that most patients with HIV infection die before
symptomatic leprosy develops.
°
143
Coinfection with HIV
Both HIV and HTLV-I infect CD4 + lymphocytes; therefore,
a possible interaction between these viruses in coinfected individuals needs to be considered [83,84]. The concern is justified
by several reports that have documented a more rapid progression of clinical immunodeficiency in coinfected subjects than
in those infected with HIV alone [85-87], although only one
of these studies distinguished HTLV-I from HTLV-II [85].
Schechter et al. [85] performed a retrospective case-control
study of 27 subjects coinfected with HIV and HTLV-I and 99
controls infected with HIV only. The authors found higher
CD4 + lymphocyte counts but significantly more advanced clinical disease in the coinfected subjects.
Conclusions
An epidemiologic and etiologic association between HTLVI infection and both ATL and HAM/TSP is clear; however,
these are the only documented sequelae, and they develop in
<5% of infected individuals. On the other hand, a sizable body
of literature now suggests that HTLV-I infection is associated
with an increased risk of three infectious diseases: strongyloidiasis, tuberculosis, and leprosy. Thus, chronic HTLV-I infection
may be immunosuppressive. HTLV-I infection does not produce the profound immunodeficiency state associated with HIV
infection, but even a mild form of immunodeficiency could
have significant medical and public health implications.
Other Infections
Case reports and small uncontrolled series have described
occasional opportunistic infections and an increased frequency
of various infections in HTLV-l-positive subjects [50, 56-60,
78]. These infections include a chronic relapsing form of eczema associated with infection with Staphylococcus aureus and
,B-hemolytic streptococci [57], Norwegian scabies and chronic
skin sores [50, 56], pulmonary cryptococcosis [58], and P.
carinii pneumonia [59]. Kaposi's sarcoma has been described
in one patient [60], and protracted chancres due to Treponema
pal/idum have been described in a rabbit model of HTLV-I
infection [78]. Of these infections, only the eczematous disease
has been shown to be more than coincidental.
An unusual infective dermatitis was first described in Jamaican children in 1966 [79], and the clinical features of this
infection were defined in 1967 [80]. Infective dermatitis is an
acute illness with severe exudation from which S. aureus and
,B-hemolytic streptococci can routinely be cultured. An association with HTLV-I infection was demonstrated in 1990 by LaGrenade et al. [57] who found that all of 14 Jamaican children
with infective dermatitis were seropositive for HTLV-I, while
none of 11 children with atopic dermatitis were seropositive.
The natural history of infective dermatitis is not well defined;
ATL may develop in a disproportionate number of subjects,
but most appear to remain hematologically normal [57, 81, 82].
Acknowledgments
The author thanks C. Fordham von Reyn, M.D., and Farley R.
Cleghorn, M.D., for their very helpful critical evaluations of this
manuscript.
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