Humoral and cellular immune response after influenza vaccination in patients with postcancer fatigue and in patients with the chronic fatigue syndrome.

Fatigue during -but also after- curative cancer treatment is a severe and
invalidating problem. The prevalence of fatigue in cancer patients, undergoing
chemo- and/or radiotherapy, has been estimated to range from 70-96%. About 20
to 40% of the disease-free cancer patients remain fatigued (at least 1 year).
These patients mention fatigue as a frequent complaint, impairing quality of
life. Previous disease and treatment characteristics seemed to be unrelated to
postcancer fatigue (PCF). However, there is some evidence that patients who are
treated with surgery only are less at risk for PCF and survivors who are
treated with more aggressive treatments are more at risk for PCF. The existing
evidence suggests that cognitive behavior therapy, especially designed for PCF,
and a home-based physical activity intervention, are effective treatment
options for PCF.
However, although it is possible to effectively treat PCF, the nature of the
underlying (neuro)physiology of PCF remains unclear. Several hypotheses about
mechanisms explaining cancer-related fatigue have already been described,
including dysregulation of brain serotonin, dysregulation of the
hypothalamic-pituitary-adrenal (HPA) axis responsiveness, disruption of the
circadian rhythm, alterations in muscle and ATP metabolism and activation of
the vagal afferent nerve. Another possible explanation for PCF is that patients
suffering from PCF have a (subtle) disturbance in the cellular and/or humoral
immune system. Activation of the immune system, as a response to the tumor or
its treatment, leads to the release of cytokines and other immune factors.
Cytokines are critical to both the innate and adaptive immune response, but
also mediate neural symptoms such as fatigue. Most of these changes in immune
parameters resolve following completion of cancer treatment, but it is possible
that (subtle) differences in the immune response remain, which could (partly)
explain the symptoms of fatigue. In 2007, Schubert et al reviewed the
association between cancer-related fatigue and inflammatory marker levels in a
quantitative way and a significantly positive correlation between
cancer-related fatigue and the levels of inflammatory markers in the
circulation was shown. Next to (subtle) differences in cytokines levels between
fatigued and non-fatigued cancer survivors, there is also evidence that there
are also variations in the prevalence of cytokine producer cells between those
two groups.

Another group of patients suffering from severe fatigue symptoms are patients
with the chronic fatigue syndrome (CFS). The estimated worldwide prevalence of
CFS is 0.4-1%. In the Netherlands, about 100.000 patients are suffering from
chronic fatigue, of which 30.000 to 40.000 suffer from CFS. In contrast to
fatigue in patients with PCF, in patients with CFS no clear precipitating
factor could be identified. CFS is present when patients suffer from severe,
persistent or continuously returning complaints of fatigue, which do not
improve noteworthy after rest and which are not the consequence of continuous
exertion, the fatigue resulted into a substantial decrease in former levels of
professional, social and/or personal functioning, the complaints cannot be
explained by a physical cause, and the complaints persist for at least 6
months. Also for patients with CFS, a cognitive behaviour therapy is designed,
which is proven to be effective, but the pathophysiological mechanism of CFS is
unclear. Hypotheses explaining CFS include morphological and metabolic
abnormalities in the brain, diminished central activation failure of muscles, a
neuroendocrine disturbance, or cognitive impairment caused by response to
specific stimuli. Another possible explanation for CFS is altered central
nervous system functioning resulting from an abnormal immune response. Studies
have sought evidence for a disturbance in immunity in people with CFS: an
alteration in cytokine profile, a decreased function of inflammatory markers, a
presence of autoantibodies, and a reduced T-cell response to specific antigens
have been reported. It is possible that in patients with CFS, (subtle)
differences in immune response could (partly) explain the symptoms of fatigue.

There seem to be similarities between patiente suffering from PCF and patients
suffering from CFS, but also differences are present between both groups. In
comparison to patients with PCF, CFS patients score more problematic with
regard to the level of fatigue, functional impairment, physical activity, pain
and self-efficacy.
The question is whether PCF and CFS could be explained by the same immunologic
pathofysiological mechanism. What have never been done before, is to compare
the immune response of patients with PCF and patients with CFS with each other
directly. By means of this proposed explorative study, we would like to improve
the understanding of the humoral and cellular immune response in patients
suffering from PCF and CFS. The most ideal situation to study the immune system
is in an activated state, like after vaccination. In this study, the influenza
vaccination will be used to activate the immune system.

By means of this study we would like to answer the following questions:
- Differs the humoral or cellular immune response after influenza vaccination
between fatigued patients (with PCF or CFS) and non-fatigued patients?
- Differs the humoral or cellular immune response after influenza vaccination
between patients with PCF and patients with CFS?

The immune response is the highest after the first vaccination. That's why this
study will focus on patients receiving the influenza vaccination in this study
for the first time. Patients and controls, who participate in this study and
who have no or now for the first time an indication for the
influenzavaccination because of their age. Ofcourse, the patients and controls
decide by themselves whether they would like to participate in this study or
not, and with that also whether they would receive the influenzavaccination or
not.

The effect of influenza vaccination on the immune response will be assessed in
20 patients with PCF and in 20 patients with CFS. As a control group for
patients with PCF, 20 patients without PCF (but with a cancer history) will
participate in the study. Additionally, 20 healthy controls will be asked to
participate in the study as a control group without a cancer history and
without fatigue symptoms. These four groups will be age- and sex-matched as
good as possible.

The study will take place in the UMC St. Radboud in Nijmegen. All patients have
been treated in this hospital for cancer (patients with PCF and patients
without PCF) or have been referred to the Nijmegen Expert Centre Chronic
Fatigue (NKCV; patients with CFS). The healthy controls will be approached by
their general practioner. A minimum age of 18 years and a maximum age of 60
years will be maintained. From 2008 on, all people who are at least 60 years of
age will be offered influenza vaccination.

Healthy controls who are suitable for this study will be approached by their
general practioner, who will explain the study and who will ask whether they
would like to receive influenza vaccination or not if they would participate in
the study.

Patients who are suitable for this study will be approached by their treatment
officer, who will explain the study and who will ask whether they would like to
receive the influenza vaccination or not and if they would participate in the
study.

In case of approval to participate in the study by the patient and/or the
healthy control, an appointment will be made at the policlinic Medical Oncology
with the research assistent. Additionally, the general practioner will be
informed about the study.

The first appointment (day 1) will take place between the second half of
October and the first half of November, because this is the period the national
influenza vaccination takes place. Where possible, the appointments will be
compared with the routine control apppointments in the UMC St. Radboud. The
patient/healthy control will be ask to bring a list of current used medicines
and of the medicines used the former two weeks.

At the policlinic will, after informed consent is signed, 103 ml blood be
collected and will the patient/healthy control complete a questionnaire about
the current use of medicines and formed vaccinations. Subsequently, the
patient/healthy control will receive the influenza vaccination by the research
assistent. The patient/healthy control will be asked to contact the research
assistent in case of influenza symptoms, in order that the severity and the
duration of the complaints can be registered.

Subsequently, on day 8 and day 22 of the study, the patient will visit the
policlinic again for blood collection, 83 ml a time, by the research assistent.

The blood collections will be combined as much as possible with the regular
blood collections. Further controls of the patients will go by the normal route
scheme at the own oncologist.

In april the research assistent will contact the patient/healthy control one
more time by phone to check whether a possible infection by influenza had taken
place or not the former 6 months.

Patients will receive, if desired, travel expenses.

The burden consists mainly out of the time investment in the visits of the UMC.
St. Radboud and the collection of blood and the influenza vaccination. At the
first day, the vaccination can cause some pain, redness or a light swelling at
the place of injection (upper arm). These symptoms will disappear spontaneously
after one or two days. The influenza vaccination cannot cause influenza.
Complaints like listlessness, headache and fever are infrequent, but can occur
the day after injection. When the exclusion criteria will be taken into
consideration, no other risks will be associated with participation.