28 1/

REPORT

~IENTIFIC GROUP ON HTLV-I INFECTIONS

1/

Convened by the

REGIONAL OFFICE FOR THE WESTERN PACIFIC OF THE

WORLD HEALTH ORGANIZATION Kagoshima. Japan 10-15 December 1988

Not for sale Printed and distributed

by the

Regional Office for the Western Pacific of the World Health Organization

Manila. Philippines March 1989

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28 SEP 1989

NOTE

The views expressed in this report are those of the participants in the Scientific Group on HTLV-I Infections and Associated Diseases and

do not necessarily reflect the policies of the World Health Organization.

This report has been prepared by the Regional Office for the Western Pacific of the World Health Organization for governments of Member States in the Region and for the participants in the Scientific Group on HTLV-I Infections and Associated Diseases, Kagoshima, Japan,

10-15 December 1988.

1.

2.

3.

INTRODUCTION

...

PROCEEDINGS ... ..

2.1 2.2 2.3 2.4 2.S

Epidemiology •••.•.••••.•••••.•••••.••.••.•

Pathomechan1s.s of HAK/TSP ••••••••.•••••..

Laboratory diagnosis of HTLV-I infection •••

Prevention and control of HTLV-I infection.

Treatment of HAM/TSP ••••••••••••••••••••••

RECOMMENDATIONS ... " ... ..

1 2 2 6 7 8 8 8 ANNEX 1 - LIST OF MEMBERS, TEMPORARY ADVISERS,

OBSERVERS AND SECRETARIAT •••••••••••• 11

ANNEX 2 - AGENDA ... ,... 19

1. INTRODUCTION

The meeting of the Scientific Group on HTLV-I Infections and Associated Diseases was held in Kagoshima, Japan, from 10 to 15 December 1988.

Dr S.T. Han, Special Representative of the Director-General, World Health Organization, gave the introductory remarks, and Dr Hiroshi Nakajima, Director-General, opened the meeting.

Dr Han pointed out that HTLV-I is reported to be highly endemic in some parts of Japan but it had now been found that the virus was endemic in many parts of the Western Pacific Region, such as Papua New Guinea, Solomons and Vanuatu.

Dr Nakajima said that the WHO Western Pacific Regional Office had taken the initiative of convening a series of meetings to focus attention on HTLV-I. In August 1987, a WHO Working Group on Viral Haemorrhagic Fever and Viral Neurological Diseases, held in

Seoul, Republic of Korea, had reviewed the epidemiological features of human retroviruses associated with neurological manifestations. A WHO/Japan Joint Conference on Integrated Strategy for the Control of AIDS and Other Human Retroviral

Infections and Hepatitis B had been held in Tokyo in October 1987.

The conference had noted that since HIV, HTLV-I and HB virus infections had similar modes of transmission, an integrated strategy for their prevention and control should be considered.

Dr Nakajima noted that HTLV-I had been isolated from

intravenous drug abusers. There was therefore great concern that the virus had moved beyond its usual confines and might have the potential to become widespread throughout the world.

The objectives of the Scientific Group were:

(1) to review the epidemiology of HTLV-I infection, HTLV-I associated myelopathy (HAM) and adult T-cell leukemis

(ATL);

(2) to review the clinical and laboratory diagnosis and case management of HTLV-I infection, HAM and ATL;

(3) to develop guidelines for prevention and control of HTLV-I infection.

Dr Mitsuhiro Osame was appointed Chairman, Dr Pamela Rodgers- Johnson, Vice Chairperson, and Dr Guy de The, Dr Gustavo Roman and Dr Yuzo Iwasaki Rapporteurs.

The list of participants and agenda are attached as Annex 1 and Annex 2 respectively.

2. PROCEEDINGS

2.1 Epidemiology

2.1.1 Mode of virus transmission

The Group recognized the existence of four modes of cell associated HTLV-I transmission:

(i) Mother to child

Mother to child transmission via breast-feeding plays a key role in transmission of HTLV-I in Japan and Jamaica. This

mechanism may play an important role in perpetuation of HTLV-I in isolated populations. Efficiency of transmission from the

infected mother to the child is estimated at between 15% and 25%.

Factors determining the risk of transmission from carrier mothers to their infants are little understood.

(ii) Blood transfusion

Blood transfusion in endemic areas is becoming a major element in horizontal transmission of HTLV-I. Studies in Japan and Martinique have demonstrated a higher risk of developing neurological complications following transfusion of HTLV-I

positive blood products after a short incubation period of about two years.

(iii) Sexual transmission

Sexual transmission with greater efficiency from male to female than from female to male may explain an increase in prevalence of HTLV-I infection in women as evidenced by an age- dependent rise in prevalence, with a marked excess of carriers over the age of 30.

(iv) Intravenous transmission via needle sharing

High prevalence of HTLV-I antibodies among intravenous drug abusers has been found in Europe and North America.

2.1.2 HTLV-I seroprevalence in the world

Countries and regions in which HTLV-I infections are endemic include Japan, Melanesia, the Caribbean and some areas of Africa.

The pattern of HTLV-I infection in endemic areas has exhibited marked clustering at racial, household and small community levels. The recent introduction of blood transfusion and intravenous drug abuse has altered and magnified the natural history of HTLV-I transmission.

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HTLV-I infection is highly endemic in some parts of Japan and it has been suggested that approximately 1.2 million HTLV-I

carriers exist in Japan, distributed from south to north. As anticipated, HTLV-I carriers in Bolivia, Brazil, Hawaii, and Peru are largely confined to people with Japanese ancestry. HTLV-I infection is virtually absent in China and the Republic of Korea.

No data exists in southern ASia.

Very high prevalence of HTLV-I infections has been reported throughout Melanesia. An atypical pattern of HTLV-I

seropositivity, even in Western Blot by radioimmune assay, is shown especially in Melanesia. Whether different serotypes or cross-reactivity with other viruses is involved needs to be determined. Many other South Pacific PolyneSian and Micronesian countries have low carrier rates or none.

In the Americas, HTLV-I has been found among blacks in the Caribbean Basin and in the south-eastern United States, in Amerindian groups in the Arctic regions and the south-eastern United States, and among Indians in Panama, Central America, the Venezuelan jungle, the Andes, Colombia and Peru.

In Europe, only the Puglia region south of Italy, has shown elevated positive HTLV-I prevalence.

Although HTLV-I is prevalent among populations of black African ancestry in the Caribbean, South America and Europe, studies in African populations have given contradictory results and low rates of infections. Further seroprevalence studies in representative samples of African populations using standardized tests will be required to define the dimensions of the problem in Africa.

2.1.3 Epidemiology of HAMjTSP

The largest number of HAMjTSP cases have been identified in Japan. The prevalence of HAMjTSP is estimated to be 1 in 1000- 2000 carriers in Japan. A high incidence of HAM/TSP is reported from Kyushu and neighbouring islands, Okinawa, and Hokkaido and is parallel to the prevalence of HTLV-I carriers in these areas. The prevalence of HAMjTSP among HTLV-I carriers in certain areas of the Caribbean and South America is reported to be 1-5%.

Cases of HAMjTSP have been reported in North America in black Caribbean migrants living in Montreal, Chicago, Boston, New York, Los Angeles, San Francisco and Miami. A few cases in Caucasians in the US have been reported.

In Central America, cases of HAMjTSP have been reported in Guatemala, El Salvador and Panama.

In the Caribbean many nations have reported the occurrence of HAM/TSP with the largest series from Jamaica, Martinique and

Trinidad and Tobago.

In South America, cases of HAH/TSP have been reported from Colombia, Peru, Chile, Paraguay and French Guiana. Unconfirmed HAH/TSP cases have been informed from Ecuador and Brazil.

In Europe, isolated cases of HAM/TSP among Caucasian patients have been identified in France and Italy.

In Africa, cases mimicking HAM/TSP have been found in Ivory Coast, Senegal, Ethiopia and South Africa. The reactivity of the sera from these patients to known HTLV-I antigens was relatively poor or absent. However, a relatively large number of HTLV-I negative endemic myeloneuropathies have been reported from Africa.

In addition, foci of high prevalence of HAM/TSP have been found in Zaire and the Seychelles. In the Far East, TSP has been reported in India but HTLV-I testing of those cases has not been

completed.

In summary, the mechanism of HTLV-I transmission and the factors responsible for its endemicity in a particular population are reasonably well established. The main challenge in the

epidemiology of HTLV-I is the current lack of appropriate seroepidemiologic data on its worldwide distribution in many areas. The lack of simple and inexpensive tests for mass

seroprevalence studies remains the most important limiting factor in the completion of these studies. Priority should be given to the study of populations where ATL and TSP or spinal paraparesis has already been shown to be present.

2.1.4 Clinical diagnosis of HAH/TSP

The causative role of HTLV-I in endemic forms of TSP

(tropical spastic paraparesis) appears to be well documented and generally recognized. The identity of HTLV-I positive TSP and HAM is also generally accepted.

Criteria for diagnosis of HAH/TSP are shown in Table 1 below.

Table 1. Diagnostic gUidelines for HAH/TSP

1. Clinical criteria

The florid clinical picture of chronic spastic paraparesis is not always seen when the patient first presents. A single symptom or physical sign may be the only evidence of early HAH/TSP.

A. Age and sex incidence

Mostly sporadic and adult, but sometimes familial, occaSionally seen in childhood; females predominant.

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B. Onset

This is usually insidious but may be sudden.

C. Main neurological manifestations

1. Chronic spastic paraparesis which usually progresses slowly, sometimes remains static after initial

progression.

2. Weakness of the lower limbs, more marked proximally.

3. Bladder disturbance is usually an early feature, and constipation usually occurs later, and impotence or decreased libido is common.

4. Sensory symptoms such as tingling, pins and needles, burning, etc. are more prominent than objective physical signs.

5. Low lumbar pain with radiation to the legs is common.

6. Vibration sense is frequently impaired, proprioception less often affected.

7. Hyperreflexia of the lower limbs, often with clonus and Babinski's sign.

8. Hyperreflexia of upper limbs, and positive Hoffmann's and Tromner signs frequent, weakness may be absent.

9. Exaggerated jaw jerk in some patients.

D. Less frequent neurological findings

Cerebellar signs; optic atrophy; deafness; nystagmus;other cranial nerve deficits; hand tremor; absent or depressed ankle jerk.

Convulsions, cognitive impairment, dementia or impaired

consciousness are rare.

E. Other neurological manifestations which may be associated with HAM/TSP

Muscular atrophy; fasciculation (rare); polymyositis;

peripheral neuropathy; polyradiculopathy; cranial neuropathy;

meningitis; encephalopathy.

F. Systemic non-neurological manifestations which may be associated with HAM/TSP

Pulmonary alveolitis; uveitis; Sjogren's syndrome;

arthropathy; vasculitis; ichthyoses; cryoglobulinemia;

monoclonal gammopathy; adult I-cell leukemia/lymphoma (ATL).

Laboratory diagnosis

1. Presence of HTLV-I antibodies or antigens in blood and cerebrospinal fluid (CSF).

2. CSF may show mild lymphocyte pleocytosis.

3. Lobulated lymphocyte may be present in blood and/or CSF 4. Mild to moderate increase of protein may be present in CSF.

5. Viral isolation when possible from blood and/or CSF.

This chronic myelopathy is predominantly spastic and with relatively limited sensory impairment, and early sphinteric dysfunction (HAM/TSP) remains the most common neurological

disease produced by HTLV-I infection. Wider spectrum of clinical features such as neuropathy, encephalopathy and polymyositis, are being recognized to be associated with HAM/TSP. Cases mimicking MS or ALS are also being reported.

2.2 Pathomechanism of HAM/TSP

A number of immunological studies on clinically and serologically confirmed cases of HAM/TSP disclosed that these patients share some immunological features commonly encountered in autoimmune diseases; polyclonal activation of T and B cell

functions. Although the CD8/CD4 ratio is not altered in the peripheral blood of the patients, an increased proportion of CD8 in the CSF resulted in the increased CD8/CD4 ratio in the CSP. A linkage of these altered immune states to the genetic background of HAM/TSP patients was also suggested. These results need further confirmation by the studies on HAM/TSP patients in other geographical locations.

Neuropathological findings of eight autopsy cases of RAM/TSP were reported. Cardinal and common pathological findings in these 8 cases were mononuclear cell infiltration, chiefly of lymphocytes in vascular and subarachnoid spaces, with occasional parenchymal infiltration. These inflammatory changes were accompanied by myelin damage with relative sparing ofaxons in the white matter, most commonly in the lateral funiculus but often extending to both the posterior and anterior funiculi. In addition, gliosis in the tissue parenchyma, hyalinoid thickening of vessel walls with

preservation of the endothelium and fibrous thickening of meninges are commonly seen. These pathological changes chiefly involve both spinal grey and white matter, most severely of the lower thoracic cord, but it may involve the cerebral white matter, cerebellar cortex and the brain stem. Identification of cell type of cell infiltrates and a search for the viral antigens in the nervous tissue need to be continued.

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HTLV-I infected lymphocytes were inoculated into marmosettes, rabbits and rats in the hope of inducing the nervous system

lesions but met with no success. Long periods of infection with HTLV-I in chimpanzees even combined with HIV, has failed to induce any neurological diseases.

2.3 Laboratory diagnosis of HTLV-I infection Screening tests

(i) Particle Agglutination Test (PA)

The particle agglutination test is used extensively in Japan to screen blood donors as well as for sero-epidemiological

studies. This test is simple and easy to perform (results known within 2 hours) and is relatively inexpensive. However, it has some limitations. In some parts of the world (Papua New Guinea and Hawaii) the PA test detects significant numbers of

individuals who may not be real positives. Therefore confirmatory tests are needed to determine true positives.

(ii) ELISA test

Several manufacturers in the United States are producing kits to be used by blood banks. The test is relatively easy to perform and is good as a screening test. However, the HTLV-I virus is grown in different lymphoid cell line for the preparation of antigen for the ELISA test and the above procedure may affect the specificity and sensitivity of the test.

The positive rates may vary from manufacturer to

manufacturer, as well as the different cut-off points between the positive and the negative samples recommended by the manufacturer.

The ELISA test therefore can only be used in some of the countries where better laboratory facilities and trained laboratory

personnel are available.

Confirmatory testes)

(i) Immunofluorescence test

Although this test may be less sensitive, it is more

specific. Therefore this test can be used as a confirmatory test provided expert training is given to individuals to read the test, as it can be very subjective. In many laboratories

immunofluorescence microscopes may not be available to do this test. However, this may not be the only limitation, as experience in interpretation of the test is of the utmost importance.

(ii) Western blot test

It is recommended that one protein coded by the Gag gene product p24 and one coded by the envelop gene product either gp46 or gp61/68 should be present to make the diagnosis of

a seropositive individual.

Atypical elucidation.

other related

patterns of seropositivity in Western blot require Whether different serotypes or cross reactivity with viruses is involved needs to be determined.

(iii) Competitive ELISA test

These have been used as confirmatory tests in some of the laboratories. However at this point with limited experience this test may not be useful as a confirmatory test, and comparative studies should be undertaken with other confirmatory tests such as Western blot or radio-immunoassay test (RIA) to assess the

validity of this test under stringent conditions.

(iv) Radioimmunoprecipitation test

This test requires the labelling of infected cells with radio-isotope, and also requires the counter for the measurement of the radioactivity of the antigen antibody reaction. This test, though sensitive, is very difficult and expensive to perform and can only be used in the reference centres to determine the true positivity of the indeterminate Western blot samples.

2.4 Prevention and control of HTLV-I infection

The Group recognized that the spread of HTLV-I infection may be controlled by elimination or restriction of breast-feeding, screening of blood and blood products for HTLV-I and health education for drug abuse and safer sexual practice.

2.5 Treatment of HAM/TSP

Active and passive exercises with rehabilitatory training programmes constitute the basic treatment with appropriate anti- spastic drugs and those for urinary problems.

Amongst the specific drugs at present prednisolone administered orally would appear the best. It has produced

beneficial effects with more than half of the patients taking it, including short-term temporary remissions.

Other types of treatment like cytotoxic drugs, anti-viral agents like AZT are undergoing evaluation.

3. RECOMMENDATIONS

The Group endorsed the recommendations made previously at the Working Group on Viral Haemorrhagic Fever and Viral Neurological Diseases, Seoul, Korea, 24-26 August 1987, and the WHO/Japan Joint Conference on Integrated Strategy for the Control of AIDS

9/10

and Human Retroviral Infections and Hepatitis B, Tokyo, Japan, 5-9 October 1987. To further stimulate the knowledge and control of HTLV-associated diseases, the following recommendations were proposed:

3.1 As HTLV-I associated myelopathy (HAM) and HTLV-I positive tropical spastic paraparesis (TSP) are clinically and

pathologically identical diseases occurring in different geographical locations, both temperate and tropical, the name

"HAM/TSP" should be used for the time being.

3.2. The Group recommended urgent dissemination of the information on HAM/TSP among physicians throughout the world in view of the high prevalence already found in Japan, the Caribbean and South America and the worldwide sporadic occurrence of the disease.

3.3 The Group recommended continuous epidemiological surveillance of HTLV-I infection and its associated disorders.

3.4. The Group recognized the occurrence of a wide spectrum of the HTLV-I associated diseases, and recommended the search for and elucidation of co-factors which precipitate and/or modify the

disease process.

3.5 The Group recommended the development of rapid, sensitive and more standardized procedures for laboratory diagnosis of the

infection by HTLV-I and further delineation of virus serotypes.

3.6 The Group recognized the four modes of HTLV-I transmission:

breast-feeding, blood transfusion, sexual intercourse and

intravenous drug abuse, and the exercise of appropriate measures to control the transmission of the virus was urged.

3.7 The Group encouraged the further development of therapeutic regimens for HAM/TSP.

LIST OF MEMBERS,

TEMPORARY ADVISERS, OBSERVERS AND SECRETARIAT

1. MEMBERS

Dr D. Babona Director

Papua New Guinea Red Cross Blood Transfusion Service Department of Health Boroko

Papua New Guinea

Dr G. de The

ANNEX 1

Laboratoires d'Epidemiologie et Immunov1rolog1e des Tumeurs Faculte de Medicine

Alexis Carrel

Rue G. Paradin-69372 Lyon, Cedex 8

France +

Dr Arw1n Diwan Associate Professor

Department of Tropical Medicine and Medical Microbiology

University of Hawaii at Manoa John A. Burns School of Medicine Leahi Hospital

3675 Kilauea Avenue Honolulu, Hawaii 96816 United States of America

Dr Y. Iwasaki Professor

Department of Neurological Sciences Tohoku University

School of Medicine 1-1 Seiryo-machi Senda! 980

Japan

Annex 1

12

Dr P. Rodgers-Johnson

Laboratory of Central Nervous System Studies, NINCDS

National Institutes of Health Bethesda, Maryland 20892 United States of America

Dr K.S. Mani

Neurological Clinic

No. 1 Old Veterinary Hospital Road Basavangudi, Bangalore

India 560 004

Dr I. Miyoshi

Professor of Internal Medicine Kochi University School of Medicine Nangoku 781-51

Japan

Dr O. Morgan

Professor of Medicine Department of Medicine

University of the West Indies Mona, Kingston 7

Jamaica West Indies

Dr S. Nagataki

Professor, of Internal Medicine Nagasaki University

Faculty of Medicine 12-4 Sakoto-machi Nagasaki

Japan

Dr K. Okochi

Clinical Laboratory and Blood Transfusion Service Kyushu University Hospital 812 Fukuoka, Higashi-ku Maidashi 8-1-1

Japan

Dr M. Osame Professor

Annex 1

Third Department of Internal Medicine Fsculty of Medicine

Kagoshima University 1208-1, Ushuko-cho Kagoshima City Japan

Dr G.C. Roman

Department of Neurology Texas Tech University Health Sciences Center School of Medicine Lubbock, Texas 79430 United States of America

Dr T. Saida Director

National Utano Hospital

8 Ondoyama-cho. Narutaki Ukyo-ku Kyoto 616

Japan

Dr S. Sonoda

Chairman and Associate Professor Department of Virology

Faculty of Medicine Kagoshima University 1208-1 Usuki-cho Kagoshima 890 Japan

Dr K. Sugamura Professor

Department of Bacteriology

Tohoku University School of Medicine 1-1 Seiryo-machi

Sendai 980 Japan

Dr K. Tajima

Aichi Prefecture Cancer Center 81-1159 Tashiro-machi

Senju-ku

Nagoya City 464 Japan

Annex 1

14

Dr K. Takatsuki Professor

Second Department of Internal Medicine Kumamoto University Medical School

I-I-I, Honjo Kumamoto 860 Japan

Dr K. Tashiro Professor

Department of Neurology Hokkaido University School of Medicine

Nishi 7, Chome 15 Jo, Kita-ku Sapporo 060

Japan

Dr J-C. Vernant

Department of Neurology La Meynard Hospital

Centre Hospitalier Regional Port de France

Martinique

Dr M. Yoshida Director

Department of Virology

Institute of Cancer Research 1-37-1 Kami-Ikebukuro, Toshima-ku Tokyo 170

Japan

Dr V. Zaninovic

Hospital Universitario de Valle

"Evarlsto Garcia"

Casilla No. 18 Cali

Colombia

Annex 1

2. TEMPORARY ADVISERS

Dr C.G. Gajdusek

Chief, Laboratory of Central Nervous System Studies, NINCDS

National Institutes of Health

Bethesda, Maryland 20892 United States of America

Dr A. 19ata President

Kagoshima University Korimoto 1-21-24 Kagoshima 890 Japan

3. OBSERVERS

Dr H. Shoji

First Department of Internal Medicine Kurume University

School of Medicine 67 Asahi-machi Kurume 830 Japan

Dr I. Maruyama

Third Department of Internal Medicine Kagoshima University

1208-1 Usuki-cho Kagoshima 890 Japan

Dr N. Ohba

Department of Ophthalmology Kagoshima University

1208-1 Usuki-cho Kagoshima 890 Japsn

Annex 1

16

Dr S. Akizuki

Department of Pathology Medical College of Oita

Idaigaoka, Hazama-cho Olta-gun 879-56

Japan

Dr E. Sato

Second Department of Pathology Kagoshima University

1208-1 Usuki-cho Kagoshima 890 Japan

Dr Y. Itoyama

Department of Neurology Kyushu University

School of Medicine

3-1-1, Maidashi, Hlgashi-ku Fukuoka 812

Japan

Dr M. Mori

Division of Internal Medicine Nagasaki Chuo National Hospital Omura, Nagasaki 856

Japan

Dr T. Tabira

National Institute of Neuroscience 4-1-1 Ogawa, Higashi-machi, Kodaira Tokyo 187

Japan

Dr K. Arimura

Third Department vf Internal Medicine Kagoshima University

1208-1, Usuki-cho Kagoshima 890 Japan

Dr Angela Manns

National Cancer Institute National Institute of Health

6130 Executive Boulevard, Ste. 434 Rockville, Maryland 208924

United States of America

Dr T. Miyamoto

Department of Bacteriology Nagasaki University

12-4 Sakoto-machi Nagasaki

Japan

4. SECRETARIAT

Dr H. Suzuki

Regional Adviser in Communicable Diseases WHO Regional Office for Western Pacific

Manila

Dr T. Umenai Director

Disease Prevention and Control WHO Regional Office for

the Western Pacific Manila

Annex 1