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Journal of Postgraduate Medicine
Medknow Publications and Staff Society of Seth GS Medical College and KEM Hospital, Mumbai, India
ISSN: 0022-3859 EISSN: 0972-2823
Vol. 49, Num. 1, 2003, pp. 31-38
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Journal of Postgraduate Medicine, Vol. 49, No. 1,
Jan-March, 2003, pp.
31-38
Symposium
An Overview of Paediatric Leishmaniasis
Kafetzis DA
Second Department of Paediatrics, University of Athens, "P. and A. Kyriakou" Children's
Hospital, Athens, Greece.
Address to Correspondence: Dimitris A.
Kafetzis, MD, University of Athens Second Department of Paediatrics, "P.
and A. Kyriakou" Children's Hospital, Athens, 11527 Greece
E-mail: kafetzis@ath.forthnet.gr
Code Number: jp03007
Abstract:
Leishmaniasis, a parasitic disease transmitted by the bite of some species
of sandflies affects various age groups depending on the infecting Leishmania species,
geographic location, disease reservoir, and host immunocompetence. Visceral
leishmaniasis is the most severe form of the disease affecting children. The
extent and presentation of the disease depend on several factors, including
the humoral and cell-mediated immune response of the host, the virulence of
the infecting species, and the parasite burden. Children are at greater risk
than adults in endemic areas. Malnutrition contributes to the development of
disease, and incomplete therapy of initial disease is a risk factor for recurrence
of leishmaniasis. Children usually present with intermittent fever, paleness,
refusal to feed or anorexia, weight loss, and abdominal distension. Splenomegaly,
hepatomegaly, lymph node enlargement, thrombocytopaenia, anaemia, leukopaenia
and hypergammaglobulinemia are the most common findings in Paediatric leishmaniasis.
Molecular methods appear to offer the promise of accurate non-invasive tools
for the diagnosis of Leishmaniasis. Till these methods are evaluated, definite
diagnosis will rely on the demonstration of the infecting parasite in various
tissues. World-wide, with the notable exception of India, pentavalent antimonial
compounds remain the most effective and the most affordable therapy for this
disease. Lipid formulations of amphotericin B were assessed as short duration
treatment and were proved to be effective. However, their cost precludes their
wide use in developing countries. Miltefosine, a new oral agent, might prove
effective, safe, and affordable. Strategies aimed at control of the micro-population
of sandflies, eradication of canine leishmaniasis, and offering personal protection
against sandfly bites, together with health education programs in developing
countries, can help control the disease. Development of an effective vaccine
remains a priority. (J Postgrad Med 2003;49:31-38)
Key Words: Children, visceral leishmaniasis, antimonials,
amphotericin, liposomal amphotericin.
Leishmaniasis, a vector-born disease caused by obligate intra-cellular protozoa
of the genus Leishmania, is capable of causing a spectrum of clinical
syndromes affecting millions of people in endemic areas of the tropics and
subtropics. It affects other regions of the world as well with the only exception
of Australia and Antarctica. The prevalence is the highest in central and south
America, southern Europe, central Africa and parts of southern and central
Asia. Leishmaniasis is transmitted by sandflies (Phlebotomus species).
In the human host, Leishmania are intra-cellular parasites that infect
the mononuclear phagocytes. When a vector (sandfly) transmits the parasite
between vertebrate hosts, usually dogs or rodents and humans, the parasites can cause
different disease manifestations. In cutaneous leishmaniasis (CL), the amastigotes
replicate in the dermis and do not spread beyond the site of the vector's bite.
The lesion often heals spontaneously. In visceral leishmaniasis (VL), the amastigotes
replicate
in macrophages of the mononuclear phagocyte system and then spread to the entire
reticuloendothelial system, resulting in "kala-azar" or they replicate
and spread in the naso-oropharyngeal mucosa, resulting in mucocutaneous leishmaniasis
(ML). Left untreated, these latter conditions result in high rates of mortality.1-4
Leishmaniasis affects various age groups depending on the infecting species,
geographic location, disease-reservoir and host immunocompetence. Although
the various species and subspecies of the genus Leishmania traditionally
have been considered either viscerotropic or dermotropic, exceptions have been
reported. Whether visceral involvement with some strains of Leishmania is
exceptional or relatively common but only rarely recognised is unknown. It
is also not known if the strains that disseminate to the viscera differ subtly
from strains that do not.5-7 Host factors, such as lack of previous
exposure to the parasite and type of immune response generated, may also play
a role in visceral dissemination of the various strains. Recently, visceral
leishmaniasis has received increasing attention, as a result of the parasite
emerging as an opportunistic pathogen among HIV-infected
patients, with the recognition of imported cases after travel to endemic areas
and with the adoption of these organisms as a model for the study of cell-mediated
immune
responses.8-10
Visceral Leishmaniasis in Children
Three epidemiological forms affecting children have been recognised. In India
and Brazil where an animal reservoir has not been identified, visceral leishmaniasis
is found in all age groups. This epidemiological form was first described in
India, and is known as the Indian type of visceral leishmaniasis. In this form
of the disease, children between 5 and 15 years of age are affected. L.
donovani is the predominant parasite of this form of Leishmaniasis in India,
while in the New World, the disease is predominantly caused by L. chagasi. In
areas with animal reservoirs, such as the Mediterranean Basin, visceral leishmaniasis
mainly affects children of 1 to 4 years of age; it is caused mainly by L.
infantum, transmitted by phlebotomine sandflies, and dogs are
the most important reservoir. The African type of VL is again caused by L.
infantum affecting older children and young adults and rodents are the
reservoir hosts.1,2,11
Visceral disease (classically known as "kala azar") is the most
devastating form of the disease and if left untreated, is fatal. It results
from systemic infection of the liver, spleen, and bone marrow. The syndrome
is characterised by the pentad of fever, hepatosplenomegaly, pancytopenia,
hypergammaglobu-linemia and weight loss. However, after infection most cases
remain asymptomatic or are associated with symptoms that eventually resolve
spontaneously.1,2,11-15
Pathogenesis
Leishmania species exist as extra-cellular flagellated promastigotes
in the guts of female sandflies, and transform to the amastigote form in animal
and human hosts. In this form, the protozoa resist phagolysosomal enzymes and
replicate within the macrophages. This allows them to spread throughout the
reticuloendothelial system of the host and live within the intra-cellular lysosomal
organelle of macrophages. It has recently been recognised that sandfly components
may enhance the ability of the promastigotes to enter macrophages and thus
increase its virulence.2,16
Pathogenesis appears related to T-cell cytotoxicity, and control of visceral
leishmaniasis depends on the magnitude of T helper 1 and multicytokine responses
early in the course of infection. During progressive Leishmania infection
in mice, Th2-type CD4 T cells expand and secrete interleukin-4,
resulting in polyclonal B-cell activation.17 Fully established
visceral leishmaniasis is associated with cellular anergy, as indicated by
negative skin tests to Leishmania antigens and in-vitro lymphocyte
transformation, which reverse to positive several months after successful
treatment.
Inappropriate antigen presentation and communication between the antigen-presenting
cells and T cells, as well as the induction of interleukins 10 and 4 may explain
this anergy. Interleukins 10 and 4 suppress, whereas interleukin-12 promotes,
interferon-γ responses. The fact that interleukin-12 and interferon-γ appear
to be important in order to achieve a favourable outcome after leishmanial
infection renders them potential adjuvants for the development of vaccines
and therapeutic regimens.18-23
Current data indicate that susceptibility to leishmaniasis is genetically
determined.19,21 The extent and presentation of the disease depend
on several factors, including the humoral and cell-mediated immune response
of the host, the virulence of the infecting species, and the parasite burden.2 However,
it has been shown that children are at a greater risk than adults in endemic
areas. Malnutrition seems to contribute to the development of the disease,
and incomplete therapy of initial disease predisposes to recurrence of leishmaniasis.1-3
Infections may heal spontaneously or may progress to chronic disease, often
resulting in death from secondary infection. If spontaneous recovery occurs,
the patient's cell- mediated immunity increases. Such patients will develop
a delayed hypersensitivity response resembling the tuberculin reaction upon
intra-dermal injection of a suspension of killed promastigotes. This is known
as the leishmanin or Montenegro test. If the individual is unable to mount
an appropriate immune response, the parasite disseminates in the reticuloendothelial
cells of the body. Alternately, the parasite may remain dormant and not present
itself until one's immune system becomes compromised.24
Clinical Presentation and Laboratory Findings
Prospective studies in northeastern Brazil have shown that approximately 12%
of infected children develop typical visceral leishmaniasis. It was also shown
that exposure to a high leishmanial burden, younger age, malnutrition, and
poverty are associated with increased probability of evolution to typical symptomatic
illness. Such studies have not been conducted in the areas of the Mediterranean
basin. It has, however, been reported that the median age at diagnosis of Mediterranean
visceral leishmaniasis is less than 3 years and that infants are frequently
affected. Typical visceral leishmaniasis usually occurs after an incubation
period, which can vary widely from 2 weeks to 8 months (usually 2-6 months),
depending on the patient's age and immune status, and the species of Leishmania.
In developing countries, young malnourished children are extremely susceptible
to develop progressive infection. In these
areas, the disease has an insidious onset with pyrexia, which is continuous or
remittent and becomes intermittent at a later stage. Sometimes, it is described
as a "double-rise fever in
24 hours". Occasionally, the disease may present with an acute onset. Children
presenting later in the course of the disease may demonstrate oedema caused by
hypoalbuminemia, haemorrhage due to thrombocytopenia or growth failure related
to the presence of chronic infection. Splenic enlargement, a finding that is
often quite prominent, along with accompanying hepatomegaly causes an abdominal
protuberance in these patients. While the disease progresses, the spleen extends
well below the costal margin; it is usually firm or hard in consistency, but
soft spleen may be encountered in
acute disease.31-36
Intermittent fever (95%), pallor (77%), refusal to feed or anorexia (40%),
weight loss (18%), abdominal distension (18%), cough (16%), vomiting (15%)
and diarrhoea (12%) were the commonest presenting complaints in a study we
conducted in southern Greece in 82 immunocompetent children with Mediterranean
leishmaniasis. Massive splenomegaly (99%) was almost universally encountered
in this study population. Hepatomegaly (85%), lymph node enlargement (39%)
and ecchymoses or gingival bleeding (2%) were the other common manifestations
noted on physical examination. The liver and spleen were usually soft and easily
palpated. The laboratory tests revealed thrombocytopenia (80%), anaemia (77%),
leukopenia (62%) and hypergammaglobulinemia (100%). There was no death reported
in this study.29 Similar findings were also reported from Italy,
southern France and Spain.5,15,24,28,30 In a study conducted in
Turkey, concerning 40 cases of VL in children, the findings were analogous.
However, the investigators also reported certain unusual manifestations in
the form of tachycardia (80%), cardiac murmur (75%), petechiae or ecchymoses
(30%), and jaundice (20%). Abdominal distension was observed in 80% of their
cases.13
Late in the course, epistaxis, and gingival bleeding caused by severe thrombocytopenia
may occur; oedema and ascites may also develop. Jaundice with mildly elevated
enzyme levels is rarely seen and is considered to be a bad prognostic sign.
As the disease progresses, children in some areas develop typical habitus:
a thin and cachetic patient with abdominal distension with skin hyperpigmentation
related to xerosis and melanocyte stimulation, alopecia and elongated eyelashes.
Petechiae and ecchymoses may be seen in the extremities. Pedal oedema is observed
more commonly in children.31,33-36 Skin lesions, which contain parasites and appear as diffuse, warty, non-ulcerative
lesions, may occur in visceral leishmaniasis. These have especially been reported
from studies carried out in Africa.35,36 Mucosal lesions in the
mouth and nose, which appear as nodules or ulcers and may lead to perforation
of the nasal septum, have been described in Sudan but are rare elsewhere.35,
36 Such findings have not been described in Greece nor have they been
reported from other areas of Southern Europe. Unusual clinical presentations
include pancytopenia without splenomegaly, generalised lymphadenopathy without
hepatosplenomegaly, massive hepatic necrosis, and retinal haemorrhages.1-3,31
Commonly encountered laboratory findings include normocytic-normochromic anaemia,
neutropenia, thrombocytopenia, hypergammaglobulinemia (as a result of polyclonal
B cell activation) and hypoalbuminemia. Serum levels of hepatic transaminases
may be elevated.13,14,27,29,30 Circulating immune complexes and
rheumatoid factor are present in the sera of most patients with visceral leishmaniasis.
Rarely, immune-complex deposition in the kidneys may lead to mild glomerulonephritis.
However, renal failure is not a feature of visceral leishmaniasis. Rare manifestations
of visceral leishmaniasis include haemophagocytic syndrome, acute hepatitis,
cholecystitis, and Guillain-Barré syndrome.2,37 Also, postkala
azar dermal leishmaniasis has been reported from India.38 It is
said to occur in approximately 10% of cases after the treatment of visceral
leishmaniasis. Lesions can develop as late as 1-2 years after treatment for
the original disease and manifest on the face, trunk or extremities, and may
persist for as long as 20 years. In Africa, it has been reported that dermal
lesions occur in only 2% of cases and tend to appear during or shortly after
the treatment and persist only for a few months.35,38 This complication
has not been reported in Mediterranean leishmaniasis. Mortality is related
to immunosuppression and secondary infections and in untreated cases mortality
ranges from 75-95%.1-4
Skin lesions are the hallmark of cutaneous leishmaniasis and these skin lesions
heal spontaneously within 2-10 months.11,39,40
In mucocutaneous leishmaniasis, known as espundia in South America,
mucosal ulcerations usually develop by metastasis rather than by local spread,
and causes disfiguring lesions over the face. It destroys the mucous membranes
of the nose, mouth, and throat. Secondary infection plays a prominent role
in the size and persistence of these ulcers. Children are rarely affected and
the progression of the disease is slow and steady but it carries a significant
mortality
rate.1-4
Recently, visceral leishmaniasis has received increasing attention, as a result
of the parasite emerging as an opportunistic pathogen among HIV-infected patients.
Diagnosis and Differential Diagnosis
Detailed diagnostic procedures for Leishmaniasis are described in an other
article in this symposium. In children, however, a definite diagnosis of visceral
leishmaniasis relies on the demonstration of Leishmania in tissue specimens
or tissue culture. The parasite can be demonstrated through direct evidence
from peripheral blood, bone marrow, or splenic aspirates. Microscopy of bone
marrow aspirates is the safest diagnostic approach for paediatric patients,
with amastigotes seen in more than 90% of cases by an experienced observer.27,29 Repeated
sampling, however, may be required. In adult patients, bone marrow microscopy
is less sensitive (~70%). The higher diagnostic efficacy of the bone marrow
examination in children is probably related to the heavier parasitisation encountered
in children. Microscopic examination of splenic aspirates offers the highest
sensitivity (up to 98%), but is associated with the risk of life-threatening
haemorrhage in cases with profound thrombocytopenia.1-4
In immunocompetent individuals, serological assays (direct agglutination,
enzyme-linked immunosorbent assay, and indirect immunofluorescence) are considered
to be sensitive for the diagnosis of visceral leishmaniasis. In a study conducted
in Brazil, the indirect immunofluorescence assay achieved sensitivity and specificity
rates close to 100% for the diagnosis of visceral leishmaniasis, with immunoglobulin
G antibodies significantly reduced after treatment.40 Recently,
a strip test employing the recombinant K39 antigen of L. chagasi was
developed. This strip test had a sensitivity of 100% and a specificity of 98%
among patients in India. [No reference cited] However, in a study from Sudan,
which compared the use of the recombinant K39 strip test with that of the recombinant
K39 enzyme-linked immunosorbent assay and the direct agglutination test, the
former gave limited sensitivity [67% versus 100%, and 91% (at > 1:1600
cut-off), respectively].41 The interpretation of serological results
is complicated by high titres observed for months or years after successful
treatment and in cases of asymptomatic infection.41 Moreover, serological
tests are positive in only half of HIV infected patients with Leishmaniasis.10
Over the past 5 years, the value of polymerase chain reaction (PCR) for the
diagnosis of visceral leishmaniasis has been assessed using different clinical
specimens (peripheral blood, bone marrow, and spleen).42,43 The
detection of persistent parasite DNA in infected tissues by means of PCR may
also
be used as a marker for the risk of relapse after initial cure. Currently,
PCR should be regarded as a promising tool, with the potential advantage of
using blood specimens rather than the conventional invasive procedures such
as splenic aspirate, bone marrow aspiration and liver biopsy.
Leishmanin skin test (Montenegro test) is of value for epidemiological studies.
The test involves an intra-dermal injection of 0.1 ml of promastigote antigen.
The reaction is interpreted after 72 hours later. It is negative during active
visceral leishmaniasis, but usually becomes positive after successful treatment.
This test is also positive in patients with previous asymptomatic infection2 and
in cases with dermal leishmaniasis.44
Differential diagnosis of Visceral leishmaniasis should include other conditions
associated with massive splenomegaly, such as malaria, tropical splenomegaly
syndrome, typhoid, miliary tuberculosis, portal hypertension, leukemias and
lymphomas, and haemolytic anaemia. Postkala azar dermal leishmaniasis should
be differentiated from yaws, syphilis, and leprosy. Sarcoidosis, midline granuloma
and histoplasmosis should be differentiated from mucocutaneous leishmaniasis.
Treatment and Prevention
For more than half a century, the pentavalent antimony compounds meglumine
antimonate (Glucantime; Aventis Pharma, Bridgewater, New Jersey, USA) and sodium
stibogluconate (Pentostam; GlaxoSmithKline, Uxbridge, Middlesex, UK) remain
the standard anti-leishmanial treatment world-wide except in India. These agents
have been used extensively in children with Mediterranean visceral leishmaniasis,
in doses of 20mg/kg daily for 30 days with initial response rates exceeding
90-95%. Relapse rates are low. Relapses are mainly observed among patients
treated with shorter courses of therapeutic agents.2,14,21,26,27 Most
children improve and become afebrile within less than a week, whereas haematological
restoration and significant subsidence of splenomegaly usually occur within
2 weeks.27,29 The main advantage of these agents is their low cost
(A 30-day course at 20mg/kg daily in an adult: Glucantime, US: $100; Pentostam,
US: $150). Disadvantages include the need for intra-muscular route of administration,
lengthy hospitalisations, and non-negligible (but transient) adverse effects,
such as electrocardiographic abnormalities, elevated levels of hepatic transaminases,
chemical pancreatitis and pneumonitis.2,29,45 In our hospital we
adopted an outpatient treatment policy in selected cases, following the evidence
of clinical improvement, drug tolerability, and socio-economic parameters indicative
of compliance.29
During the past decade, the large-scale failure (up to 64%) of pentavalent
antimonial agents in patients from India prompted their complete abandonment
as first-line agents in this area and an urgent need was felt for the development
and assessment of alternative agents. Recent data indicate that resistance
may also become a problem in Sudan.46 Currently, amphotericin B
and its lipid formulations amphotericin B cholesterol dispersion (Amphotec;
Sequus Pharmaceuticals Inc., Menlo Park, California, USA), amphotericin B lipid
complex (Abelcet; The Liposome Company Inc., Princeton, New Jersey, USA), and
liposomal amphotericin B (AmBisome; Gilead, Foster City, California, USA),
are highly active against visceral leishmaniasis in India, with long-term cure
rates exceeding 90% to 95%.
Conventional amphotericin B requires prolonged administration (1mg/kg on
an alternate-day schedule over a 30-day period). It is associated with renal
toxicity necessitating monitoring of renal function. The drug is expensive,
too. Therefore, for areas outside India this drug does not offer any obvious
advantages over pentavalent antimonial agents.47 Several studies
using the three-lipid formulations of amphotericin B have been conducted in
adults and children world-wide. Some studies have indicated that even 5-10
day course of therapy may be enough for successful treatment of visceral leishmaniasis.47,48 In
1997, the United States Food and Drug Administration approved AmBisome (in
the dose of 3 mg/kg/day on days 1-5, 14, and 21) for the treatment of visceral
disease in immunocompetent children. The estimated cost for the drug itself
for a 25-kg patient is US $2,068. Thus, the wide use of commercial lipid formulations
of amphotericin B is prohibitively expensive in developing countries, where
they are needed the most. In these countries, the simple mixing of amphotericin
B with a commercially available fat emulsion was proposed (at 2 mg/kg on an
alternate-day regimen for a total of 10 days), and has proved to be more affordable
and equally effective.48,49
Amphotericin B and its lipid formulations are administered by infusion, which
necessitates intravenous fluid administration through relevant equipment. Fever
and chills are commonly experienced during infusion, and monitoring of renal
function is required. Recently, a single-dose infusion of AmBisome (at 5 and
15 mg/kg) was assessed in patients in India, with cure rates approaching 100%49,50 It
is, however, feared that short courses may contribute to the emergence of drug
resistance.48-50 Aminosidine was also recently evaluated in India,
where a 21-day course at 16-20 mg/kg/day was as
sociated with cure rates of up to 97%. These data make aminosidine another
attractive first-line agent for this area, with a proposed cost similar to
that of conventional amphotericin B. The cost of aminosidine therapy is second
only to amphotericin B-fat emulsion.47 Out-patient treatment with
one of the aforementioned regimens appears to be feasible for those patients
who manifest clinical improvement and tolerate therapy, but always bear the
risk of non-compliance and partial treatment.
Oral treatment for visceral leishmaniasis has only recently become a reality,
with the introduction of miltefosine. Treatment with this agent (at 100-150
mg/day for 28 days) has been almost 100% effective and well-tolerated in phase
I/II studies conducted in India among newly diagnosed patients or patients
unresponsive to pentavalent antimonial agents. Studies of miltefosine in young
children are underway.47
The preferred anti-leishmanial agent as well as the optimal duration of treatment
in HIV-co-infected patients has not yet been established. A successful clinical
response is achieved in up to two-thirds of cases, regardless of the agent
used (pentavalent antimonial agents, conventional or lipid formulations of
amphotericin B). The management of such patients is further complicated by
the fact that most of the initially cured patients are likely to relapse within
the following 6-12 months. To date there are no uniform guidelines regarding
the use of maintenance regimens to prevent relapse2,10
In recent trials, daily interferon-γ injections combined with pentavalent
antimonial agents were shown to accelerate the clinical response and achieve
a long-term cure in approximately two-thirds of cases unresponsive to treatment
with pentavalent antimonial compounds alone. However, in a randomised, controlled
study conducted in India, where resistance to pentavalent antimonial agents
is high, the same combination given for 28 days failed to show such adjunctive
activity in terms of long-term cure.47 Again, the cost of approaches
including cytokine immunotherapy is prohibitive in developing areas.
Several vaccines against leishmaniasis are being tested; however, none of
them is in routine use. Vaccines using killed or live-attenuated parasites
or recombinant DNA-derived components, such as antigens and peptides, have
been tested with varying success.20,21,51 A recent approach is the
development of a vaccine using sandfly salivary gland proteins, capable of
inducing strong protection in the skin against leishmanial infection. Data
from mouse models are promising.52 Ideally, sandfly components could
be incorporated in a vaccine, together with parasite antigens. The presence of
numerous parasite and sandfly species constitutes the main setback of such
a strategy. Of equal significance
is the definition of the population that is unable to elicit a protective immune
reaction against leishmanial infection, where a vaccination policy is needed
the most.20,21
In the developing countries, the use of personal protection with repellants,
permethrin-impregnated bed nets, and suitable clothing significantly reduced
the domestic transmission of leishmanial infection53,54 Also, individuals
are advised to, ideally, sleep on the second floor of a building, since the
flight of the sandfly is limited to 10 feet. The eradication of all stray and
domestic infected dogs is also required for a successful intervention on the
reservoir-vector-host chain.28 Noxious plants are also harmful to
sandflies, and may provide local protection against sandfly bites.55
Table 1
Conclusion
The number of cases of leishmaniasis is increasing, mainly
because of man-made environmental changes that increase human exposure to the
sandfly vector. The recent increase in the canine population because
of socio-cultural changes, and the movement of susceptible populations into
endemic areas also contribute to the increased incidence.56 Visceral
leishmaniasis should be suspected in children who present with specific manifestations,
no matter where they live, and even without a history of travel to an endemic
area. The diagnosis should be established, mainly by the demonstration of
Leishmania in tissue specimens. Molecular techniques could soon change this
situation considering the promise they have shown in the diagnosis of other
infectious diseases. Several advances in the treatment of visceral leishmaniasis
have been accomplished during the past few years. The management of each
case depends on the efficacy and toxicity profile of the therapeutic agents
that are affordable within a specific area and also on host factors. Control
of sandflies through residual insecticides spraying, and improved environmental
sanitation and personal protective measures, have been proved essential.
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