Flu Shots

Since the Chiron factory in Liverpool has been closed for health and safety
reasons, and it supplies about a half of the flu shots for America there is
sure to be a shortage this season. You are right in thinking that flu shots are
something of a gamble. The surface antigens of flu change pretty regularly
and since the vaccine has to be prepared months in advance it is always
possible that a particular vaccine will not protect against this season's outbreak.
I have had flu twice in my life; in 1957 I had Asian flu and in 1969 I had
Russian flu. Both were pretty bad and I wouldn't wish it on anyone (however,
lots of people think that they have flu when all it is, is a heavy cold.)

I have never had a flu vaccine, and I have not caught it since. All patients
with CLL have an impaired immune response, and those who have had it longest
or most severely have the worst immune response. Because of this it is quite
common for the flu vaccine to offer no protection in more than half of
patients (unless you want to volunteer for the ranitidine experiment). Some may
get some benefit, so doctors tend to say, "Well it can't do any harm" when
quizzed about whether a patient should have it. However some people to get
reactions.

The thing that protects most CLL patients from flu is herd immunity. This
means that if most of the community is protected, CLL patients don't have anyone
to catch it from.
 

This is a complicated question that has been troubling a lot of list members.

First: Influenza is a serious disease that usually spreads out of Asia in
great waves. Every ten years or so there is a major change in the surface
membrane antigens that means that previous immunity to the virus, whether from
vaccination or prior infection, is rendered pretty useless. Unless this occurs,
people who have been previously vaccinated or had the flu (real flu, not just
a heavy cold) are somewhat protected. There are minor changes every year and
because of this it is standard advice to recommend that the most vulnerable
(the elderly, diabetics, health care workers etc) are vaccinated every year.
Patients who have the flu are at risk because they can get a super-infection
caused by a bacterium which can cause a fatal pneumonia

Second: Aren't CLL patients among the most vulnerable? Yes they are, but all
patients with CLL have impaired immune systems. Evidence suggests that fewer
than half CLL patients get a useful response after vaccination.

Third: Even so, isn't it worth vaccinating for the sake of the 45% who will
respond? Absolutely, that's why doctors say you may as well have it. It won't
do any harm. (Although some patients get reactions as we have seen from
messages to the LIST. Remember that the symptoms of flu are caused by the body's
immune reaction to the virus, not principally by the virus killing cells. All
those fevers, shakes, headaches etc are because the body is fighting the
infection).

Fourth: What kinds of patients are most likely to get benefit from flu jabs?
Those with early stage disease (stage 0) who still have their spleens and
have never received treatment. Splenectomy, chemotherapy (especially
fludarabine), antibody therapy, and advanced CLL all reduce the chance of responding to
a flu jab.

Fifth: What about rituximab? Rituximab is a monoclonal antibody that targets
CD20, which is on all B-cells. B-cells are the cells that are necessary to
make antibody. If you knock out your B-cells you won't be able to respond to a
flu jab. The B cells remain 'knocked out' for a long time after rituximab,
sometimes up to 2 years. Rituximab is used to treat a number of diseases caused
by antibody such as ITP and AIHA. That's why many doctors advise patients
not top have a flu jab if they are having rituximab. BUT this is theory not
backed up by clinical trials. That's why some doctors advise to go ahead with
the flu jabs anyway because without a clinical trial you can't be sure of
anything, no matter how good the theory.

Sixth: What about ranitidine? Ranitidine has been shown in one clinical
trial to more than double the response rate to vaccination. BUT it was quite a
small trial, it was against a different vaccine (a conjugate Haemophilus
influenza vaccine - this is a bacterium, not the virus that causes flu), and
no-one has repeated the study and it has not been generally adopted in CLL. I
think this study should be repeated with flu vaccine.

Seventh: This year with such a shortage of flu vaccine, especially in
America, there will be less herd immunity against flu, and therefore there may be a
greater risk to CLL patients. If a patient consulted me about whether they
should have a flu vaccine I should recommend that they had it under cover of
ranitidine 300mg twice daily for 90 days starting on the day of the vaccination.
Ideally this would be organised as a prospective clinical trial with blood
taken before and after to see if the jab had produced any antibodies.
 

Ranitidine and Pneumonia

This LIST is first with the news!

This is the report of a study in this week's JAMA. It comes from the
Netherlands and the first author is Robert JF Laheij.

What they did was to retrieve data from an electronic database containing
the medical records of approximately half a million patients of 150 general
practitioners. After excluding patients who had not been studied long enough
they eventually looked at the records of 364 683 people. Of these 10 177 had
received treatment with H2 antagonists (drugs like ranitidine) and 12 337 had
received treatment with PP!s (drugs like omeprazole). Among those currently
taking one or other of the drugs there were 185 cases of pneumonia, but there
were 292 cases after stopping their use. The excess risk of developing pneumonia
with H2 antagonist treatment was 1 case of pneumonia for every 508 people
treated.

The characteristics of patients on antacids compared to the controls were as
follows: they were more likely to have chronic obstructive lung disease, more
likely to have stomach cancer, more likely to have lung cancer and more
likely to be on immunosupopressant drugs.

Comment:

This is an epidemiological study and as such there is a danger of confusing
association with cause. The authors have interpreted the results as meaning
that the lack of gastric acid has allowed the stomach to become colonized by
bacteria, which then infect the lungs. The authors draw attention to some of
the possible flaws in their study. 1. the diagnosis of pneumonia was not
established scientifically in most cases, but just on clinical grounds without
X-rays or microbiology. 2. The fact that patients taking any medication would be
more closely monitored than those not taking medicines, and therefore more
likely to be diagnosed. 3. It is possible that patients prescribed an antacid
never took the drug or even filled in the prescription. 4. Perhaps the
symptoms of pneumonitis were mistaken by the general practitioner for peptic ulcer
pain and inappropriately treated with antacids.

However, I think a misleading result is less likely to be due to one of
these than to the possibility that what was making them prone to pneumonia was
also making them more likely to be prescribed an antacid. Here are two
possibilities 1. Steroids are frequently prescribed for asthma and chronic
bronchitis. Both are also regularly complicated by pneumonia. Steroids cause peptic
ulceration. Antacids are frequently prescribed to patients on steroids either
prophylactically or as a consequence of gastric symptoms. 2. Regurgitation and
inhalation of acid at night is one of the causes of community acquired
pneumonia. patients with acid regurgitation are usually treated with antacids.

Thus while they may be right in their speculation, there are reasons for the
association.

So where does that leave the patient with CLL who wants a flu jab? As I keep
saying the response to influenza vaccination in CLL patients is poor. It is
unlikely to cause harm, but, especially in patients with more advanced
disease and in those who have been treated with fludarabine and/or rituximab, or
with Campath, vaccination is unlikely to be protective. There is one published
study showing a doubling of the response rate from 43% when ranitidine 300mg
twice daily was given for 90 days after vaccination. There is also one
unpublished study showing a lesser (and non significant) improvement when half this
dose was used for a shorter time period. Now we have another factor to add
to the pot. The Dutch study which shows an association between taking antacids
and getting pneumonia. The risk is small (1 case of pneumonia for every 508
people treated) and we don't know whether the ranitidine is causative (it may
be that people who are given ranitidine are given it for conditions which
themselves are prone to lead to pneumonia).
 

September 2005

My advice about flu vaccines is currently this.

It is worth getting the flu vaccine even though more than half of CLL patients will get no benefit from flu vaccines especially those who have advanced disease, or have had treatment, or have had mild disease for a long time; so it is important to take other precautions. Try and benefit from 'herd immunity'. This means that your likely contacts should be vaccinated. Wash hands regularly - at least 6 times a day, and especially after touching things that other people have touched. Use alcohol swabs to sterilise objects in common use like telephones and keyboards.

There is one strategy that has been shown to double the response rate to vaccines: Take Ranitidine (ZANTAC) 300mg twice daily for 90 days during the vaccination period. Have the flu vaccine on days 1 and 45 of the Ranitidine. This has not been confirmed or refuted, but an attempt to do so using a lower doses of ranitidine showed some effect but not a large enough one to be statistically significant.

Take Tamiflu if you catch flu and if a relative catches flu get them to take it as well.

Vaccination against pneumonia with pneumovax is even less likely to work - response rate about 0%. Instead use the conjugated vaccine Prevenar. Again, use the Ranitidine trick.