- Email: [email protected]
Influenza vaccine and FDG-PET
CORRESPONDENCE
Author’s reply Sir—Ricardo Bastos makes the important point that physical examination is but one component of the clinical method. Done and interpreted in the light of other clinical information (most notably, the patient’s history), physical examination raises as many questions as it answers. Hence the importance of “rationalising” the entire clinical method, not merely the handson part. I agree with Bastos that more research is needed. Binu John and Smitha Thomas suggest that my reported incidence of pivotal physical findings might have been exaggerated because I was aware of previous examiners’ findings and patients’ responses to initial management. I agree that such information might have contextualised my approach to some patients, perhaps intensifying my focus on specific aspects of their examination. This information might have made my examination smarter, but it did not alter the fact that the findings were there to be found. The tricky methodological issue they and Bastos raise concerns the interdependent nature of the various types of information gleaned from the clinical method. One cannot quantify the effect of physical examination per se without studying a control group in whom physical examination is not done. In my view, such a study in sick inpatients is unethical. I hope John and Thomas will reconsider their opinion that physical examination soothes the psyche more than it reveals the soma. John Ioannidis raises the question of false positives and their potential to instigate unnecessary, potentially harmful, interventions. These outcomes comprised five of the 26 pivotal findings I reported. I cannot exclude the possibility that some of my own findings were also falsely positive. I found no evidence of this, but that is Ioannidis’s point: how could I, without an unbiased impeccable referee to certify my own accuracy? I can only say that I am more than willing to repeat my study if Ioannidis would kindly supply the referee. In addition, Ioannidis’s point about predictive values is well taken. But is he aware that “low risk” medical patients are not easy to find in US hospitals today? If I understand his point, then all the more reason to promote skilled physical examination in such settings. Finally, I am struck by the contrast between the letters of F J C Millard and John Ioannidis. I admire the clinical expertise of physicians in many developing countries who accomplish so much with so little technological
2024
activation. It might be very sensible for PET centres to check with their patients for recent immunisations, and delay imaging if this has occurred.
support. Unfortunately, lacking that support, some of them cannot verify the clinical outcomes that validate their expertise. I hope they can soon, as their countries develop. But I do not hope that their “development” extends to a point where they question seriously “whether whole subspecialties of our profession are useful”. In medicine, scepticism—not nihilism—stimulates progress.
D McCool, J R Buscombe, *A J W Hilson Department of Nuclear Medicine, Royal Free Hospital, London NW3 2QG, UK (e-mail: [email protected]) 1
Brendan Reilly Cook County Hospital, Room 2129, 1901 West Harrison Street, A-1502, Chicago, IL 60612, USA (e-mail: [email protected])
Iyengar S, Chin B, Margolick JB, Sabundayo BP, Schwartz DH. Anatomical loci of HIVassociated immune activation and association with viraemia. Lancet 2003; 362: 945–50.
Authors’ reply
Sir—D McCool and colleagues raise important points about the potential of recent vaccinations to confound diagnosis of metastases in regional nodes that drain injection sites. We did not generate a complete time-course of node activation, but did show strong signal 3 and 5 days after immunisation. This finding is remarkably consistent with the kinetics of lymphocyte activation and proliferation in well studied mouse models, in which cells undergo roughly 12 rounds of division within nodes, then move to the circulation 10–16 days after immunisation.1,2 It is also consistent with the recovery of recently activated lymphocytes in human circulation 14 days after immunisation. This said, there must be some variability among individuals, and between primary and anamnestic immunisations with regard to onset and duration of node activation. We want to define these kinetics but have no clear data at this time. Waiting at least 4 weeks after vaccination before using PET to diagnose tumour-involved nodes should minimise false positives from vaccine immunity, but might delay treatment. Repeat scanning at 2 and 4 weeks would be more informative, but logistically difficult. The situation can be even more confounding than the typical cases of vaccinees we described. Our first
Influenza vaccine and FDG-PET Sir—The paper by Sujatha Iyengar and colleagues (Sept 20, p 945)1 is fascinating in what it shows about the degree of metabolic activity produced in lymph nodes by viral infection. Although the major part of their work is on HIV, the fact that they showed that influenza vaccine produces lymphatic activation is of major clinical significance. The primary clinical use of fluorodeoxyglucose positron-emission tomography (FDG-PET) is in oncology, particularly for staging. This technique is most likely to be required in older age groups—the same patients who are most likely to have had recent influenza vaccine (indeed the UK government is encouraging this). The situation could therefore easily arise where an FDG-PET study is done on, say, a patient with carcinoma of the breast or lymphoma, who had had recent immunisation. Uptake identified in axillary lymph nodes might then be falsely assumed to be due to tumour. Clearly this would have a major effect on staging and subsequent therapy. Iyengar and colleagues do not give any time-scale for the duration of this
Coronal
R
L
R
L
Transaxial
R
L
R
L
FDG uptake in cervical axillary lymph nodes (two section depths) 5 days after first influenza vaccination Vaccination in left arm, FDG infusion in right.
THE LANCET • Vol 362 • December 13, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet publishing Group.
Author’s reply Sir—Ricardo Bastos makes the important point that physical examination is but one component of the clinical method. Done and interpreted in the light of other clinical information (most notably, the patient’s history), physical examination raises as many questions as it answers. Hence the importance of “rationalising” the entire clinical method, not merely the handson part. I agree with Bastos that more research is needed. Binu John and Smitha Thomas suggest that my reported incidence of pivotal physical findings might have been exaggerated because I was aware of previous examiners’ findings and patients’ responses to initial management. I agree that such information might have contextualised my approach to some patients, perhaps intensifying my focus on specific aspects of their examination. This information might have made my examination smarter, but it did not alter the fact that the findings were there to be found. The tricky methodological issue they and Bastos raise concerns the interdependent nature of the various types of information gleaned from the clinical method. One cannot quantify the effect of physical examination per se without studying a control group in whom physical examination is not done. In my view, such a study in sick inpatients is unethical. I hope John and Thomas will reconsider their opinion that physical examination soothes the psyche more than it reveals the soma. John Ioannidis raises the question of false positives and their potential to instigate unnecessary, potentially harmful, interventions. These outcomes comprised five of the 26 pivotal findings I reported. I cannot exclude the possibility that some of my own findings were also falsely positive. I found no evidence of this, but that is Ioannidis’s point: how could I, without an unbiased impeccable referee to certify my own accuracy? I can only say that I am more than willing to repeat my study if Ioannidis would kindly supply the referee. In addition, Ioannidis’s point about predictive values is well taken. But is he aware that “low risk” medical patients are not easy to find in US hospitals today? If I understand his point, then all the more reason to promote skilled physical examination in such settings. Finally, I am struck by the contrast between the letters of F J C Millard and John Ioannidis. I admire the clinical expertise of physicians in many developing countries who accomplish so much with so little technological
2024
activation. It might be very sensible for PET centres to check with their patients for recent immunisations, and delay imaging if this has occurred.
support. Unfortunately, lacking that support, some of them cannot verify the clinical outcomes that validate their expertise. I hope they can soon, as their countries develop. But I do not hope that their “development” extends to a point where they question seriously “whether whole subspecialties of our profession are useful”. In medicine, scepticism—not nihilism—stimulates progress.
D McCool, J R Buscombe, *A J W Hilson Department of Nuclear Medicine, Royal Free Hospital, London NW3 2QG, UK (e-mail: [email protected]) 1
Brendan Reilly Cook County Hospital, Room 2129, 1901 West Harrison Street, A-1502, Chicago, IL 60612, USA (e-mail: [email protected])
Iyengar S, Chin B, Margolick JB, Sabundayo BP, Schwartz DH. Anatomical loci of HIVassociated immune activation and association with viraemia. Lancet 2003; 362: 945–50.
Authors’ reply
Sir—D McCool and colleagues raise important points about the potential of recent vaccinations to confound diagnosis of metastases in regional nodes that drain injection sites. We did not generate a complete time-course of node activation, but did show strong signal 3 and 5 days after immunisation. This finding is remarkably consistent with the kinetics of lymphocyte activation and proliferation in well studied mouse models, in which cells undergo roughly 12 rounds of division within nodes, then move to the circulation 10–16 days after immunisation.1,2 It is also consistent with the recovery of recently activated lymphocytes in human circulation 14 days after immunisation. This said, there must be some variability among individuals, and between primary and anamnestic immunisations with regard to onset and duration of node activation. We want to define these kinetics but have no clear data at this time. Waiting at least 4 weeks after vaccination before using PET to diagnose tumour-involved nodes should minimise false positives from vaccine immunity, but might delay treatment. Repeat scanning at 2 and 4 weeks would be more informative, but logistically difficult. The situation can be even more confounding than the typical cases of vaccinees we described. Our first
Influenza vaccine and FDG-PET Sir—The paper by Sujatha Iyengar and colleagues (Sept 20, p 945)1 is fascinating in what it shows about the degree of metabolic activity produced in lymph nodes by viral infection. Although the major part of their work is on HIV, the fact that they showed that influenza vaccine produces lymphatic activation is of major clinical significance. The primary clinical use of fluorodeoxyglucose positron-emission tomography (FDG-PET) is in oncology, particularly for staging. This technique is most likely to be required in older age groups—the same patients who are most likely to have had recent influenza vaccine (indeed the UK government is encouraging this). The situation could therefore easily arise where an FDG-PET study is done on, say, a patient with carcinoma of the breast or lymphoma, who had had recent immunisation. Uptake identified in axillary lymph nodes might then be falsely assumed to be due to tumour. Clearly this would have a major effect on staging and subsequent therapy. Iyengar and colleagues do not give any time-scale for the duration of this
Coronal
R
L
R
L
Transaxial
R
L
R
L
FDG uptake in cervical axillary lymph nodes (two section depths) 5 days after first influenza vaccination Vaccination in left arm, FDG infusion in right.
THE LANCET • Vol 362 • December 13, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet publishing Group.