Association between HTLV-1 infection and adverse health outcomes: a systematic review and meta-analysis of epidemiological studies

Summary

Background

Human T-cell lymphotropic virus type 1 (HTLV-1) is a human retrovirus that causes a lifelong infection. Several diseases, including an aggressive form of leukaemia, have been designated as associated with HTLV-1, whereby having HTLV-1 is a necessary condition for diagnosis. Beyond these diseases, there is uncertainty about other health effects of HTLV-1. We aimed to synthesise evidence from epidemiological studies on associations between health outcomes and HTLV-1.

Methods

For this systematic review and meta-analysis, we searched Embase, MEDLINE, MEDLINE In-Process, and Global Health for publications from their inception to July, 2018. We included cohort, case-control, and controlled cross-sectional studies that compared mortality or morbidity between people with and without HTLV-1. We excluded studies of psychiatric conditions, of symptoms or clinical findings only, of people who had undergone blood transfusion or organ transplant, and of population groups defined by a behavioural characteristic putting them at increased risk of co-infection with another virus. We extracted the risk estimates (relative risks [RRs] or odds ratios [ORs]) that reflected the greatest degree of control for potential confounders. We did a random-effects meta-analysis for groups of effect estimates where case ascertainment methods, age groups, and confounders were similar, presenting pooled estimates with 95% CIs and prediction intervals.

Findings

Of the 3318 identified studies, 39 met the inclusion criteria, examining 42 clinical conditions between them. The adjusted risk of death due to any cause was higher in people with HTLV-1 when compared with HTLV-1-negative counterparts (RR 1·57, 95% CI 1·37–1·80). From meta-analysis, HTLV-1 was associated with increased odds of seborrheic dermatitis (OR 3·95, 95% CI 1·99–7·81), Sjogren's syndrome (3·25, 1·85–5·70), and, inversely, with lower relative risk of gastric cancer (RR 0·45, 0·28–0·71). There were a further 14 diseases with significant associations or substantially elevated risk with HTLV-1 from single studies (eczema [children]; bronchiectasis, bronchitis and bronchiolitis [analysed together]; asthma [males]; fibromyalgia; rheumatoid arthritis; arthritis; tuberculosis; kidney and bladder infections; dermatophytosis; community acquired pneumonia; strongyloides hyperinfection syndrome; liver cancer; lymphoma other than adult T-cell leukaemia-lymphoma; and cervical cancer).

Interpretation

There is a broad range of diseases studied in association with HTLV-1. However, the elevated risk for death among people with HTLV-1 is not explained by available studies of morbidity. Many of the diseases shown to be associated with HTLV-1 are not fatal, and those that are (eg, leukaemia) occur too rarely to account for the observed mortality effect. There are substantial research gaps in relation to HTLV-1 and cardiovascular, cerebrovascular, and metabolic disease. The burden of disease associated with the virus might be broader than generally recognised.

Funding

Commonwealth Department of Health, Australia.

Introduction

Human T-cell lymphotropic virus type 1 (HTLV-1) was the first human retrovirus to be discovered, in the early 1980s.¹ It has been found to be endemic in diverse regions of the world and to cause a lifelong infection, primarily of T-lymphocytes. Although most people living with HTLV-1 infection are asymptomatic, severe and potentially fatal complications can develop. It became apparent soon after the discovery of HTLV-1 that certain diseases have a strong association with HTLV-1 infection. An early finding was that a minority of people with HTLV-1 infection developed an aggressive haematological cancer, now known as adult T-cell leukaemia-lymphoma (ATL).² The pathological features of ATL were not seen in people without HTLV-1 infection, so the disease was effectively defined by the presence of this infection. HTLV-1 was also found to be associated with a chronic spastic paraparetic syndrome; this and other neurological manifestations of HTLV-1 infection have been defined as HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP).³ The lifetime risk of developing ATL in people with HTLV-1 has been estimated to be 2–7% whereas the risk of developing HAM/TSP is 0·25–3%.⁴

Research in context

Evidence before this study

We searched Embase, Global Health, and MEDLINE with the terms “HTLV-1” and “epidemiology” to identify all articles in any language published from inception to July, 2018, assessing the health effects of human T-cell lymphotropic virus type-1 (HTLV-1). While previous reviews of the health effects of HTLV-1 have focused on specific organ systems or disease states such as dermatological and neurological manifestations, HTLV-1-associated myelopathy or tropical spastic paraparesis, and adult T-cell leuekaemia-lymphoma (ATL), we found no comprehensive assessment of the scope and extent of morbidity associated with HTLV-1. We systematically reviewed the literature to address this gap.

Added value of study

We found in a meta-analysis that HTLV-1 infection is associated with an increased risk of death compared with those without HTLV-1 (relative risk 1·57, 95% CI 1·37–1·80). The risk is higher in younger age groups, possibly due to fewer competing causes of death. Our review highlighted a dearth of robust evidence of the morbidity associated with HTLV-1 that might explain this increased mortality. There is evidence of low to moderate quality showing that people with HTLV-1 have increased odds of developing seborrheic dermatitis; eczema; bronchitis, bronchiectasis, and bronchiolitis (analysed together); urinary tract infections; and lymphoma other than ATL. Evidence for associations between HTLV-1 and all other conditions studied was assessed to be very low quality.

Implications of all the available evidence

Our findings clearly show that people with HTLV-1 are at a higher risk of death than their HTLV-1-negative counterparts, but reasons for this are not well understood. There might be serious health effects of the virus that have not been sufficiently studied. Epidemiological studies are needed in this area, but are challenging because of the range of possible outcomes associated with the virus, difficulties in ascertaining time of acquisition and duration of infection, and the diversity of factors that might moderate the immunological response to the virus and need to be taken into account in study design. International collaboration to overcome these challenges and to design and implement studies that can compare outcomes across different settings and in different population groups is urgently needed.

Although clinical entities corresponding to ATL and HAM/TSP had long been recognised, the discovery of their strong association with HTLV-1 led to the two diseases being defined as uniquely caused by HTLV-1. Subsequent clinical research sought to examine associations between HTLV-1 infection and several other diseases. Through this research, subcategories of two other previously known diseases were defined to be uniquely due to HTLV-1, in the sense that the presence of HTLV-1 infection was a necessary diagnostic criterion: uveitis and infective dermatitis.5, 6

A recent surge of interest in optimising the prevention and treatment of HTLV-1 infection and its complications has highlighted the need for robust systematic information on the health impacts of HTLV-1.⁷ We have therefore done a comprehensive review of the evidence from epidemiological studies about associations between HTLV-1 and adverse health outcomes. It is important to note that once the presence of HTLV-1 becomes a necessary diagnostic criterion for a disease, it is no longer possible to study the magnitude of the association between that disease and HTLV-1 infection. We therefore restricted our focus to clinical disease entities and outcomes for which HTLV-1 is not a necessary diagnostic criterion.