Human T-Lymphotropic Virus type 1c subtype proviral loads, chronic lung disease and survival in a prospective cohort of Indigenous Australians

Abstract

Background: The Human T-Lymphotropic Virus type 1c subtype (HTLV-1c) is highly endemic to central Australia where the most frequent complication of HTLV-1 infection in Indigenous Australians is bronchiectasis. We carried out a prospective study to quantify the prognosis of HTLV-1c infection and chronic lung disease and the risk of death according to the HTLV-1c proviral load (pVL).

Methodology/principal findings: 840 Indigenous adults (discharge diagnosis of bronchiectasis, 154) were recruited to a hospital-based prospective cohort. Baseline HTLV-1c pVL were determined and the results of chest computed tomography and clinical details reviewed. The odds of an association between HTLV-1 infection and bronchiectasis or bronchitis/bronchiolitis were calculated, and the impact of HTLV-1c pVL on the risk of death was measured. Radiologically defined bronchiectasis and bronchitis/bronchiolitis were significantly more common among HTLV-1-infected subjects (adjusted odds ratio = 2.9; 95% CI, 2.0, 4.3). Median HTLV-1c pVL for subjects with airways inflammation was 16-fold higher than that of asymptomatic subjects. There were 151 deaths during 2,140 person-years of follow-up (maximum follow-up 8.13 years). Mortality rates were higher among subjects with HTLV-1c pVL ≥1000 copies per 105 peripheral blood leukocytes (log-rank χ2 (2df) = 6.63, p = 0.036) compared to those with lower HTLV-1c pVL or uninfected subjects. Excess mortality was largely due to bronchiectasis-related deaths (adjusted HR 4.31; 95% CI, 1.78, 10.42 versus uninfected).

Conclusion/significance: Higher HTLV-1c pVL was strongly associated with radiologically defined airways inflammation and with death due to complications of bronchiectasis. An increased risk of death due to an HTLV-1 associated inflammatory disease has not been demonstrated previously. Our findings indicate that mortality associated with HTLV-1c infection may be higher than has been previously appreciated. Further prospective studies are needed to determine whether these results can be generalized to other HTLV-1 endemic areas.

Fig 1. Recruitment based on discharge diagnosis.

Subjects with a discharge diagnosis of bronchiectasis were examined by chest high-resolution computed tomography, which confirmed the diagnosis in 104 cases and revealed bronchitis/bronchiolitis in 33 cases (bronchitis alone, 20; bronchitis/bronchiolitis, 12; bronchiolitis alone, 1). Other diagnoses included emphysema (3) and pulmonary embolus (1). No cause of chronic cough could be found in 13 cases.

Fig 2. HTLV-1c proviral load compared between asymptomatic subjects, bronchiolitis/bronchitis and bronchiectasis.

Subjects with chronic airways disease were examined by chest high resolution computed tomography. Median (IQR) HTLV-1c pVL for subjects with bronchiolitis/bronchitis (2.69 (0.82, 3.43) log₁₀ copies per 10⁵ PBL) and bronchiectasis (2.69 (1.57, 3.49) log₁₀ copies per 10⁵ PBL) were significantly higher than that of the asymptomatic group (1.48 (-0.001, 2.97) log₁₀ copies per 10⁵ PBL)(asymptomatic vs bronchiectasis, p = 0.001; asymptomatic vs bronchitis/bronchiolitis, p = 0.042). Asymptomatic subjects exclude: i) those with other HTLV-1 associated conditions (infective dermatitis, 2; probable HAM/TSP, 2; uveitis, 2; crusted scabies, 4; ATL; 1), ii) five subjects with a discharge diagnosis of bronchiectasis without radiological evidence of bronchiectasis, bronchitis or bronchiolitis and iii) three subjects who presented with neurological symptoms for whom HAM/TSP could not be excluded due to cognitive impairment.

Fig 3. Estimated survival according to HTLV-1 proviral load.

Includes 533 HTLV-1 uninfected subjects, 212 subjects with low HTLV-1c proviral load (<1000 copies per 10⁵ peripheral blood leukocytes) and 95 subjects with high HTLV-1c proviral load (≥1000 copies per 10⁵ peripheral blood leukocytes).

Fig 4. Cumulative death rate due to bronchiectasis.

Estimated using competing-risks Cox regression among 533 HTLV-1 uninfected subjects, 212 subjects with low HTLV-1 proviral load (<1000 copies/10⁵ peripheral blood leukocytes) and 95 with high HTLV-1c proviral load (≥1000 copies/10⁵ peripheral blood leukocytes).