- Email: [email protected]
CD8 ratio and lung cancer risk – Authors' reply
Correspondence
CD4/CD8 ratio and lung cancer risk
in which CD4/CD8 ratios of 0·25 or less within 1 year before lung cancer diagnosis showed an association of borderline statistical significance (presence of CD4/CD8 ratios of 1 or more were too rare to allow comparison in our smaller study; table). However, as this association was absent 1–2 years before lung cancer diagnosis (OR=1·07, 95% CI 0·49–2·36), and because we could not rule out confounding by missing or insufficient stratification by smoking intensity or duration in this highly tobacco exposed population, we chose not to highlight this finding in our conclusions.
In their recent article in The Lancet HIV, Keith Sigel and colleagues1 suggest a role for low CD4/CD8 ratios in targeting high-risk groups for lung cancer prevention. However, even if the link between CD4/CD8 ratio and lung cancer proves causal, potential for risk stratification should be tempered. Most patients do not reach CD4/CD8 ratios of 1 or more, but are in the range for which Sigel and colleagues1 show no meaningful risk difference. Furthermore, the small relative risk associated with the extreme CD4/CD8 of 1 or more category (HR=2·6) should be put into context with the highly prevalent exposure of smoking, for which the relative risk in current smokers (HR=8·5 in Sigel and colleagues1) hides a much stronger risk stratification by smoking intensity or duration. Sigel and colleagues 1 report that their literature review revealed “no studies in which the relation of CD4/CD8 ratios and risk of lung cancer was examined”. Yet we published a case-control study of lung cancer in the Swiss HIV Cohort Study2
We declare no competing interests.
*Gary M Clifford, Mauro Lise, Silvia Franceschi, Alexandra U Scherrer cliff[email protected] International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France (GMC, ML, SF); Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (AUS) 1
Sigel K, Wisnivesky J, Crothers K, et al. Immunological and infectious risk factors for lung cancer in US veterans with HIV: a longitudinal cohort study. Lancet HIV 2016; 4: e67–73.
Lung cancer
Controls
N
%
N
OR (95% CI) %
CD4/CD8 ≥0·50
22*
32·4%
140*
42·8%
1
0·25–0·49
26
38·2%
120
36·7%
1·38 (0·74–2·57)
<0·25
20
29·4%
67
20·5%
2·15 (1.00–4·59)
0
··
10
··
Unknown Smoking Never
2
3·8%
71
27·1%
1
Former
6
11·5%
63
24·0%
3·22 (0·63–16·6)
Current
44
84·6%
128
48·9%
<30 pack years
16
36·4%
62
50·8%
11·5 (2·42–54·6)
≥30 pack years
28
63·6%
60
49·2%
15·9 (3·67–69·1)
··
75
Unknown pack years Unknown
0 16
14·4 (3·36–62·1)
6 ··
A case-control study of 68 lung cancers and 337 matched controls in The Swiss HIV Cohort Study.2 OR=odds ratio. *Three patients with lung cancer (4·4%) and 26 controls (8·0%) had CD4/CD8 ratios ≥1.
Table: Relative risk of lung cancer by CD4/CD8 ratios within 1 year before cancer diagnosis and smoking
www.thelancet.com/hiv Vol 4 March 2017
2
Clifford GM, Lise M, Franceschi S, et al. Lung cancer in the Swiss HIV Cohort Study: role of smoking, immunodeficiency and pulmonary infection. Br J Cancer 2012; 106: 447–52.
Authors’ reply We appreciate the comments of Gary Clifford and colleagues and regret our oversight in not citing the work from the Swiss HIV Cohort Study that previously evaluated the CD4/CD8 ratio as a lung cancer risk factor in HIV-infected people. However, the findings from our two studies seem to cross-validate this measure as an independent predictor of lung cancer. Despite the relatively low hazard ratio associated with the CD4/CD8 ratio, we believe it is premature to dismiss its potential usefulness in an HIV-specific lung cancer risk prediction model. Although we agree that smoking clearly is the primary predictor of lung cancer, the CD4/CD8 ratio (along with history of bacterial pneumonia) may provide relevant supplementary information. In fact, lung cancer risk factors with modest associations, such as family history of lung cancer or history of chronic obstructive pulmonary disease, have been included in established lung cancer prediction models for the general population.1 Similarly, the CD4/CD8 ratio and history of bacterial pneumonia may deserve consideration in future HIV-specific prediction modelling. Additionally, as control of viraemia continues to improve in the HIVinfected population, the distribution of the CD4/CD8 ratio is likely to shift toward values of 1 or more, perhaps improving discrimination. Finally, a low CD4/CD8 ratio has been associated with immune senescence in HIVuninfected people.2 Confirmation of the CD4/CD8 ratio as a lung cancer risk factor among HIV-infected people might warrant investigation for risk prediction in uninfected people.
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Correspondence
We declare no competing interests.
Keith Sigel, Robert Dubrow [email protected].
1
Tammemagi CM, Pinsky PF, Caporaso NE, et al. Lung cancer risk prediction: Prostate, Lung, Colorectal And Ovarian Cancer Screening Trial models and validation. J Natl Cancer Inst 2011; 103: 1058–68.
2
Strindhall J, Skog M, Ernerudh J, et al. The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study. Age 2013; 35: 985–91.
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA (KS); Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
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www.thelancet.com/hiv Vol 4 March 2017
CD4/CD8 ratio and lung cancer risk
in which CD4/CD8 ratios of 0·25 or less within 1 year before lung cancer diagnosis showed an association of borderline statistical significance (presence of CD4/CD8 ratios of 1 or more were too rare to allow comparison in our smaller study; table). However, as this association was absent 1–2 years before lung cancer diagnosis (OR=1·07, 95% CI 0·49–2·36), and because we could not rule out confounding by missing or insufficient stratification by smoking intensity or duration in this highly tobacco exposed population, we chose not to highlight this finding in our conclusions.
In their recent article in The Lancet HIV, Keith Sigel and colleagues1 suggest a role for low CD4/CD8 ratios in targeting high-risk groups for lung cancer prevention. However, even if the link between CD4/CD8 ratio and lung cancer proves causal, potential for risk stratification should be tempered. Most patients do not reach CD4/CD8 ratios of 1 or more, but are in the range for which Sigel and colleagues1 show no meaningful risk difference. Furthermore, the small relative risk associated with the extreme CD4/CD8 of 1 or more category (HR=2·6) should be put into context with the highly prevalent exposure of smoking, for which the relative risk in current smokers (HR=8·5 in Sigel and colleagues1) hides a much stronger risk stratification by smoking intensity or duration. Sigel and colleagues 1 report that their literature review revealed “no studies in which the relation of CD4/CD8 ratios and risk of lung cancer was examined”. Yet we published a case-control study of lung cancer in the Swiss HIV Cohort Study2
We declare no competing interests.
*Gary M Clifford, Mauro Lise, Silvia Franceschi, Alexandra U Scherrer cliff[email protected] International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France (GMC, ML, SF); Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland (AUS) 1
Sigel K, Wisnivesky J, Crothers K, et al. Immunological and infectious risk factors for lung cancer in US veterans with HIV: a longitudinal cohort study. Lancet HIV 2016; 4: e67–73.
Lung cancer
Controls
N
%
N
OR (95% CI) %
CD4/CD8 ≥0·50
22*
32·4%
140*
42·8%
1
0·25–0·49
26
38·2%
120
36·7%
1·38 (0·74–2·57)
<0·25
20
29·4%
67
20·5%
2·15 (1.00–4·59)
0
··
10
··
Unknown Smoking Never
2
3·8%
71
27·1%
1
Former
6
11·5%
63
24·0%
3·22 (0·63–16·6)
Current
44
84·6%
128
48·9%
<30 pack years
16
36·4%
62
50·8%
11·5 (2·42–54·6)
≥30 pack years
28
63·6%
60
49·2%
15·9 (3·67–69·1)
··
75
Unknown pack years Unknown
0 16
14·4 (3·36–62·1)
6 ··
A case-control study of 68 lung cancers and 337 matched controls in The Swiss HIV Cohort Study.2 OR=odds ratio. *Three patients with lung cancer (4·4%) and 26 controls (8·0%) had CD4/CD8 ratios ≥1.
Table: Relative risk of lung cancer by CD4/CD8 ratios within 1 year before cancer diagnosis and smoking
www.thelancet.com/hiv Vol 4 March 2017
2
Clifford GM, Lise M, Franceschi S, et al. Lung cancer in the Swiss HIV Cohort Study: role of smoking, immunodeficiency and pulmonary infection. Br J Cancer 2012; 106: 447–52.
Authors’ reply We appreciate the comments of Gary Clifford and colleagues and regret our oversight in not citing the work from the Swiss HIV Cohort Study that previously evaluated the CD4/CD8 ratio as a lung cancer risk factor in HIV-infected people. However, the findings from our two studies seem to cross-validate this measure as an independent predictor of lung cancer. Despite the relatively low hazard ratio associated with the CD4/CD8 ratio, we believe it is premature to dismiss its potential usefulness in an HIV-specific lung cancer risk prediction model. Although we agree that smoking clearly is the primary predictor of lung cancer, the CD4/CD8 ratio (along with history of bacterial pneumonia) may provide relevant supplementary information. In fact, lung cancer risk factors with modest associations, such as family history of lung cancer or history of chronic obstructive pulmonary disease, have been included in established lung cancer prediction models for the general population.1 Similarly, the CD4/CD8 ratio and history of bacterial pneumonia may deserve consideration in future HIV-specific prediction modelling. Additionally, as control of viraemia continues to improve in the HIVinfected population, the distribution of the CD4/CD8 ratio is likely to shift toward values of 1 or more, perhaps improving discrimination. Finally, a low CD4/CD8 ratio has been associated with immune senescence in HIVuninfected people.2 Confirmation of the CD4/CD8 ratio as a lung cancer risk factor among HIV-infected people might warrant investigation for risk prediction in uninfected people.
e103
Correspondence
We declare no competing interests.
Keith Sigel, Robert Dubrow [email protected].
1
Tammemagi CM, Pinsky PF, Caporaso NE, et al. Lung cancer risk prediction: Prostate, Lung, Colorectal And Ovarian Cancer Screening Trial models and validation. J Natl Cancer Inst 2011; 103: 1058–68.
2
Strindhall J, Skog M, Ernerudh J, et al. The inverted CD4/CD8 ratio and associated parameters in 66-year-old individuals: the Swedish HEXA immune study. Age 2013; 35: 985–91.
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA (KS); Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
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www.thelancet.com/hiv Vol 4 March 2017