To compare the convalescent antibody response to invasive Haemophilus influenzae type b (Hib) disease between conjugate vaccine immunised and unimmunised children, to look for evidence of priming for immunologic memory. Methods: Unmatched case-control study in the UK and Eire1992-2001 and Victoria, Australia 1988-1990. A total of 93 children were identified as having invasive Hib disease following three doses of conjugate vaccine in infancy through post licensure surveillance throughout the UK and Eire; 92 unvaccinated children admitted to an Australian paediatric hospital with invasive Hib disease were used as historical controls. Convalescent serum was taken for measurement of Hib antibody concentration, and clinical information relating to potential disease risk factors was collected. The geometric mean concentrations of convalescent Hib antibodies were compared between immunised and unimmunised children, using raw and adjusted data. Results: Hib conjugate vaccine immunised children had higher serum Hib antibody responses to disease (geometric mean concentration (GMC) 10.81 µg/ml (95% CI 6.62 to 17.66) than unimmunised children (1.06 µg/ml (0.61 to 1.84)) (p < 0.0001). However, following adjustment for the significant confounding influences of age at presentation and timing of serum collection, a difference persisted only in children presenting with meningitis (vaccinated GMC 3.78 µg/ml (2.78 to 5.15); unvaccinated GMC 1.48 µg/ml (0.90 to 2.21); p = 0.003). Conclusions:

Higher antibody responses to invasive Hib disease in vaccinated children with meningitis reflect priming for immunologic memory by the vaccine. Although a majority of children in the UK are protected from Hib disease by immunisation, the relative roles of immunologic memory and other immune me chanisms in conferring protection remain unclear. Keywords: Haemophilus; immunologic memory; vaccine; conjugateAbbreviations: DTP, diphtheria-tetanus-pertussis; GMC, geometric mean concentration; Hib, Haemophilus influenzae type b; HRU, Haemophilus reference unit; PHLS, Public Health Laboratory Service; PRP; polyribosylribitol phosphate


Emerging Diseases

http://www.infectiousdiseasenews.com/200111/frameset.asp?article=Influenzae=.asp

New Haemophilus influenzae pathogen may be emerging Non-b serotypes of Haemophilus influenzae may be replacing Hib as a serious pathogen.

November 2001

SALT LAKE CITY  While Haemophilus influenzae type b (Hib) has been nearly eliminated as a major cause of serious disease in children, other serotypes, especially H. influenzae type a, may have acquired virulence traits and may be emerging as disease-causing pathogens. A recent report in Pediatrics described 5 cases of H. influenzae type a, 2 of which were strikingly reminiscent of disease caused by Hib, said the report. In 2 other cases, infections were similar to Hib infections, but different enough to suggest that 2 distinct clones of H. influenzae type a may be circulating concurrently.


Case reports In December 1998, a previously healthy 6-month-old girl presented to her doctor with lethargy, irritability and poor oral intake for 1 day, following episodes of altered consciousness and peripheral cyanosis. Upon admission to the hospital, her blood pressure was 40/20 mm Hg, pulse was 210 beats/min and her tympanic temperature was 39.4° C; there was purpura present on the nose, ear and legs, and petechiae on her face and trunk. Medical history revealed that she had received 3 doses of Hib conjugate vaccine.

The infant required intubation and mechanical ventilation with fluid support and was given intravenous cefotaxime (Claforan, Aventis), vancomycin and gentamicin. Laboratory testing revealed a white blood count (WBC) of 4,900/mm3, hematocrit 27.5% and a platelet count of 35,000/mm3. Cultures of the cerebrospinal fluid (CSF) and blood grew H. influenzae type a. Treatment was further complicated by renal failure, purpura fulminans and subdural empyema; soft-tissue necrosis ultimately required the amputation of 2 toes, said the report.

The second patient, a 1-year-old girl, was admitted to the hospital in June 1999 with a 3-day history of vomiting, fever, irritability, diarrhea and seizures. The infant also had received 3 doses of Hib conjugate vaccine. An initial exam of the 1-year-old showed that she was toxic appearing and minimally responsive. CSF was cloudy; the WBC was 1,660/mm3, red blood count 70/mm3, glucose 34 mg/dl and protein levels were 300 mg/ml. Cultures of the CSF and blood grew H. influenzae serotype a.

The second patient's hospitalization was complicated by aseptic necrosis of the right femoral head and prolonged fever. Following 4 weeks of treatment with cefotaxime, she was discharged with evidence of reduced hearing and regression of fine and gross motor skills. Epidemiology and infectivityThere had been no reported cases of invasive disease caused by H. influenzae type a in Utah between 1991 and 1998. However, between November 1998 and October 1999, there were 4 reported cases in children ranging from 6-13 months of age. All cases displayed bacteremia and meningitis, and 3 had prolonged fever, subdural empyema and aseptic necrosis of the hip ? common markers for Hib. A review of laboratory records for the same period revealed a fifth patient who grew H. influenzae type a on pure culture. Previously reported cases of H. influenzae type a occurred exclusively in patients older than 5 years. Serotype a strains isolated from 3 of the patients demonstrated the IS1016-bexA deletion that has been described in invasive type a and type b strains. DNA sequencing, assisted by primers specific to IS1016 and bexA, amplified a 362 base-pair sequence that confirmed the  finding.

Three H. influenzae type a strains with the IS1016-bexA deletion may have recombined with a circulating Hib strain because Haemophilus strains are transformable. Most virulent Hib strains contain a 1,198 base-pair sequence that removes a portion of IS1016 and bexA, promoting gene amplification, resulting in an increase in the production of capsules and increasing the virulence of Hib. The areas where IS1016 and bexA are usually found are surrounded by transposable elements, further suggesting the possibility of a recombinant H. influenzae type a strain. The 2 other patients lacked the IS1016-bexA deletion, but nevertheless suffered invasive disease due to H. influenzae type a, the report
stated.


For more information:
Adderson E, Byington C, Spencer L, et al. Invasive serotype a Haemophilus influenzae infections with a virulence genotype resembling Haemophilus influenzae type b: emerging pathogen in the vaccine era?
Pediatrics. 2001;108(1):e18.

 When I checked this website
 http://www.wyeth.com/content/ShowLabeling.asp?id=105 this is what I found. Is this not the case now? It still contains mercury?
 
 Haemophilus b Conjugate Vaccine (Diphtheria CRM 197 Protein Conjugate)  HibTlTER is a sterile solution of a conjugate of oligosaccharides of the  capsular antigen of Haemophilus influenzae type b Haemophilus b) and  diphtheria CRM 197 protein (CRM 197 ) dissolved in 0.9% sodium  chloride. The oligosaccharides are derived from highly purified capsular polysaccharide, polyribosylribitol phosphate, isolated from Haemophilus b strain Eagan grown  in a chemically defined medium (a mixture of mineral salts, amino acids, and  cofactors). The oligosaccharides are purified and sized by diafiltrations  through a series of ultrafiltration membranes, and coupled by  reductive  amination directly to highly purified CRM 197-1,2 CRM 197 is a nontoxic  variant of diphtheria toxin isolated from cultures of orynebacterium  diphtheriae C7 (ß197) grown in a casamino acids and yeast extract- based  medium that is ultrafiltered before use. CRM 197 is purified through  ultrafiltration, ammo-nium sulfate precipitation, and ion-exchange  chromatography to high purity. The conjugate is purified to remove unreacted protein, oligosaccharides, and reagents; sterilized by filtration;  and  filled into vials.  HibTlTER is intended for intramuscular use.  The vaccine is a clear, colorless solution. Each single dose of 0.5 mL is  formulated to contain 10 µg of puri-fied Haemophilus b saccharide  and  approximately 25 µg of CRM 197 protein. Multidose vials contain thimerosal  (mercurial derivative) 1:10,000 as a preservative. The potency of HibTITER  is determined by chemical assay for polyribosylribitol.

The Perilous Haemophilus or is it.....pneumonia - Hilary Butler

http://www.vaccination.org.uk/m/butler7.html

The Perilous Haemophilus
or is it.....pneumonia

By Hilary Butler

July 1996

"CHILDREN SICKER AND LOTS MORE ATTENDING STARSHIP HOSPITAL"

So said the NZ Herald, 26 Dec 1995, A3. What has that to do with the title of this article?

There appears to me a coincidence which is rather remarkable, and I probably wouldn’t have twigged to it, except that the NZ Herald, 15 April 1988, A2, had this heading: "COT DEATH INCREASE ‘APPALLING’" which discussed the "appalling" increase in the number of cot deaths throughout Auckland in 1987, especially in July, the worst month on record. Shirley Tonkin was quoted as saying: "We are just appalled by this increase, and we do not know why it is happening."

The cot deaths increase occurred THREE MONTHS after the introduction of the nationwide blanket administration of the first Hepatitis B vaccine immediately after birth.

Interesting too, that a Department of Health memo dated 21 March 1988 circulated to all hospital and Area Health Boards, detailed that the first injection should be delayed until shortly before discharge home in the case of babies of healthy mothers because: "Minor side effects from the first H-B-VAX injection in a newborn baby may be confused with more serious ill health."

In 1988 the IAS and I were run off our feet with mothers who had distressed babies after this vaccine – and those were only from that 1–5% of the population who, according to the Health Department, knew about our  existence. I heard from a nurse whose career was ruined by the hepatitis B vaccine, and from Public Health nurses who had had the vaccine and the following winter had had health problems never previously experienced.

Even more interesting was the fact that shortly after that memo, it was considered that the first shot should be given at six weeks.

The telephone line between Dr Ralph Edwards (then the Adverse Reactions doctor in Dunedin) and I was hot for 18 months about complaints from the toddler catch-up campaign and newborn babies. It’s all fact – and mentioned inside one of the fancy reports filed in obscurity somewhere in the Health Department.

What has that to do with the first heading about ‘Children sicker’ in Auckland?

There is a saying that those who don’t heed history are destined to repeat past mistakes.…

When the 26/12/95 NZ Herald article appeared, I read the fine print to find that from the beginning of July 1994 to the end of October 1995, there was a 23% increase in youngsters being brought into hospital and a 15% increase in admissions. This occurred just over one year after the introduction of TETRAMUNE in this country and two years after the introduction of ProHIBit (Hib vaccine for 18 month children and older), and in the year when the Health Department had flooded the media with reports of how the cases of Hib had fallen to rock bottom. We were told that this vaccine would ease the total work load of the paediatric staff but here we see more, sicker children than ever before.

BUT, I hear you say, there is no direct time connection with the Hib vaccine as was alleged with Hepatitis B. Read on! In the latest article: "Doctors are noticing that the proportion of very young children admitted is getting higher and that generally, children seem to be sicker when they arrive."

Interestingly they mentioned an increase in cases of pneumonia, asthma, meningococcal disease, fevers and bronchiolitis….that the reasons weren’t clear, but "lack of money to pay doctor’s bills could be a factor." That was the same reason they used in 1988 to explain the increase in cot death. The article went on to state that two Starship paediatricians are, meanwhile, probing the pneumonia increases.

What is the evidence linking pneumonia in the NZ Herald article heading with the Haemophilus vaccine?

One of the most direct (yet dismissed) pieces of research is in Paediatric Infectious Diseases Journal, December 1993, Vol. 12, 981 – 5, where there was an article looking at the safety of the Haemophilus vaccine in Kaiser, USA, from 1 November 1990, to 26 July 1991. The initial analysis of babies given TETRAMUNE (the one in use in New Zealand) showed that these children appeared to have a higher rate of hospitalisation for pneumonia than children who were given Hib and DPT in separate shots. (It’s a shame there wasn’t a third more valid control – children who had received no vaccines at all.) The article commented:

"This initial association was believed most probably to be a result of chance alone. The [Tetramune] vaccine offers the convenience of a single combined vaccine... " (p. 981).

"In addition to having an effective vaccine it is also important to administer the vaccine in a way that encourages parental and physician acceptance and minimises trauma to the infants receiving the vaccine." "... The additional injections are associated with additional administration costs at each visit. Parents may also be reluctant to subject their infants to multiple injections at the same time. This either generates unnecessary return visits or reduces compliance with recommended vaccination schedules." (pg. 982.)

So what did the trial authors do?

"In this study there was no significant difference for rates of medical adverse events as observed from emergency visits between the two vaccine groups. However, a statistically significant increased risk of pneumonia was seen after Tetramune. To investigate this possible association further analyses were undertaken...Because of the known overlap between the diagnoses of pneumonia and bronchiolitis in clinical practice in this age group, the charts of all children with these respiratory diagnoses were reviewed by a single observer who was blinded to the vaccine status of these children." – pg. 985.

This analysis showed no significant difference in the rates of pneumonia between the two groups. The article then said:

"It was concluded that...the single observed association in the automated data of pneumonia with receipt of Tetramune was most probably caused by misclassification of the diagnoses in the automated data set, or by chance alone. Tetramune would appear to offer the convenience of a single combined
vaccine offering protection... "

The authors seemed very eager to talk about the logistical and financial advantages of TETRAMUNE, and I couldn’t help wondering if this was a case of re-working the data to fit the desired outcome. What would have happened if another evaluation was done by a paediatrician opposed to the use of Hib?

I filed this article under my ‘think’ pile until the December 1995 NZ Herald article, when I went back to the pile to find out when Kaiser introduced TETRAMUNE. 1989 was the first year that TETRAMUNE, and other new Hib vaccines were approved for use in children under 18 months and, by the end of 1991, nearly 75% of children under two years of age had received the Hib vaccine, some separately and some together because they weren’t sure about it.

The time lapse between the introduction of Tetramune and the increase in pneumonia in Starship is the same as the time lapse had been in the Kaiser study (and in Finland).

Is this a coincidence?

TETRAMUNE did what they said it would. It seemed to knock out Hib. The Kaiser study (Arch Ped. Adol. Med. Jan 1994 pg. 54) did admit that the rates of Haemophilus had been falling in the two, four and six month age group, previously unvaccinated, for some time before its introduction...yet it was amongst this very group of babies that the study was done for the safety of TETRAMUNE – the same vaccine we use in New Zealand.

Bells started ringing in my head. Some years ago, the first Swedish study of the Japanese acellular pertussis (whooping cough) vaccine was abruptly stopped because a larger number of serious infections and deaths were occurring in the vaccinated group than the unvaccinated. The raw data repeatedly came up with PNEUMONIA and MENINGOCOCCAL MENINGITIS.

But acellular pertussis is a DIFFERENT vaccine. True. So

what’s going on here? First, here is some easy history you should know, and some other "coincidental" pieces of the jigsaw that need to be placed...

CRASH COURSE IN HAEMOPHILUS HISTORY.

Have you ever wondered why the name Haemophilus INFLUENZAE? A bit contradictory for a bacteria, don’t you think?

About 1888 Robert Pfeiffer isolated the organism from the sputum of patients with influenza and, for the next 30 years, the medical community assumed that Haemophilus caused the ’flu. It wasn’t until the 1918 – 19 flu pandemic that it became accepted that Haemophilus was a part of the normal bacterial flora in the upper respiratory tract and not necessarily the cause of respiratory disease. (pg. 300, VACCINES (BOOK) Harcourt Brace Jovanovich, 1988). The name remains a testimony to the misconceptions of the past.

Another interesting historical question regarding Haemophilus is: "Can we tell who will become sick as a result of H. Influenzae infection?"

The answer to that is "yes and no":

"The reports of genetic marker associations with invasive Hib disease risk and responses to vaccines support the view that genetic factors may influence disease susceptibility."

Trouble is that the immunologists haven’t figured out enough to be able to say "you, you and you" yet. We know that certain groups are more LIKELY to get it but that also applies to meningitis caused by other than Hib as well. People who have immune system problems are more likely to get bacterial meningitis but the groups that can actually be pinpointed are few and far between.

"Academic", say the researchers. Why waste more money when a vaccine is now here to solve all clinical ills?

In February 1993 IAS newsletter readers were alerted to a seeming connection between the use of the Haemophilus vaccine and an increase in Pneumococcal disease in an article entitled DREAMERS AND THEIR APPRENTICES. To recap the story until that time, this is what had happened:

The June 1992 issue of Newsletter from the Journal of Paediatric Infectious Disease (JPID) stated:

"THE PERILOUS PNEUMOCOCCUS. We have great concern for the increasing prevalence of relatively or absolutely penicillin resistant pneumococci coupled with the increased relative frequency of pneumococcal diseases as a result of universal Haemophilus vaccination."

"We need new agents that are active against these strains, especially WHEN THEY CAUSE INFECTION OF DIFFICULT TO TREAT SITES LIKE THE MENINGES OR HEART VALVES."

After considerable discussion, on 27 July 1992, Dr Morris and I sent a letter to JPID:

"RELATIONSHIP BETWEEN PREVALENCE OF PNEUMOCOCCAL MENINGITIS AND UNIVERSAL
HAEMOPHILUS INFLUENZA VACCINATION"

To the Editors:

In the Paediatric Infectious Disease Journal newsletter (1992;18:6) concern was expressed "...for the increasing prevalence of relatively or absolutely penicillin resistant pneumococci coupled with the increased relative frequency of pneumococcal diseases as a result of universal Haemophilus vaccination. For example, we recently managed a nine month old infant with pneumococcal meningitis who failed to respond adequately to ceftriaxone therapy."

These sentences could be taken to mean that concern was prompted by an increase in prevalence of diseases including meningitis due to infection with penicillin-resistant pneumococci and that the increase resulted from universal Haemophilus vaccination. How or why one circumstance resulted in the other is not given in the quoted sentences nor given elsewhere in the newsletter note. That prior administration of Haemophilus vaccine might increase on rare occasions susceptibility to pneumococcus infection was not entertained.

The sentences might also mean that universal Haemophilus vaccination resulted in a decrease in Haemophilus diseases including meningitis and that the void was filled by an increase in pneumococcal diseases caused by antibiotic resistant pneumococci. If this is the explanation, then solution of one problem has given rise to another and this new problem is difficult to treat with available antibiotics which gives rise to a new need: antibiotics that are active against pneumococcal strains that invade difficult to treat sites like the meninges and heart valves.

This apparent one step forward-one step backward situation is reminiscent of similar problems that accompanied early use in the 1960’s of inactivated adenovirus vaccines to prevent respiratory diseases caused by adenovirus types 3, 4 and 7. The vaccines were highly effective in preventing disease caused by these types, but not effective in preventing respiratory diseases caused by the other 40 or more adenoviruses that moved in to replace types 3, 4 and 7. Soon after this situation was recognised, use of adenovirus vaccines, except for use in military personnel, was abandoned. It might be well when assessing the overall value of the current program of universal Haemophilus vaccination, to keep in mind the earlier adenovirus vaccine experience.

J. Anthony Morris, Ph.D. Bell of Atri, Inc.

Hilary Butler IAS."

On 29th July (quick response!) the reply came back, which said:

"We will have an item of clarification in the September Newsletter concerning the potentially confusing statement in The Perilous Pneumococcus item."

Before the "clarification" came another item came up – one which was already in press at the time of the above correspondence:

August 1992 JPID:

Kaiser study 130,000 children. "Only six vaccinated children developed invasive Haemophilus disease, five of whom had received only one dose. In a Letter to the Editors in the October issue, Leggiadro and colleagues will show a substantial reduction in cases of invasive Haemophilus disease admitted to LeBonheur Children’s Hospital, Memphis, TN from 1982 – 1991. OF CONCERN WAS A TWOFOLD INCREASE IN THE RATE OF PNEUMOCOCCAL DISEASE IN 1991." (emphasis mine)

Note the year – 1991, which was in the 12 – 24 month period after the introduction of this vaccine. Just like in Auckland.

Then came the ‘clarification’.

September 1992: JPID: "A CHOICE OF WORDS: Dr J. Anthony Morris asked what we meant by "increased relative frequency of Pneumococcal disease as a result of Haemophilus vaccination that appeared in our item THE PERILOUS PNEUMOCOCCUS in the June 1992 newsletter; our statement reflects the dramatic decline in the number of cases of invasive Haemophilus disease we and many others have experienced in the last 12 months or longer as a result of vaccination. We did not mean to imply that the absolute number of cases of pneumococcal disease would increase: rather, the frequency relative to Haemophilus disease would become greater as fewer cases of the latter are encountered."

On 10 April, after some interesting medical articles, Dr Morris fired off another letter reminding Dr Nelson of our previous letter, including a copy of it, and adding:

"Knowledge of past events is of value if it is of use in predicting future events. Thus in the 3 April issue of LANCET is a paper "population-based study of Non-typable Haemophilus Influenzae Invasive Disease in children and Neonates". It reports "Infections due to (non-capsulated) H influenzae strains are, after the implementation of Hib vaccines, likely to persist and represent a substantial proportion of the serious infections caused by this species... Furthermore, the relative importance of such organisms may increase because of the general introduction of type b polysaccharide vaccines, which will greatly diminish invasive Hib disease, but not systemic infection caused by NST of H influenzae of other capsular types.

"The episode in the 1990’s with Hib vaccine is reminiscent of the experience in the 1960’s with adenovirus vaccine. This is more so now than in July 1992.

"In light of the new information you might now think that messages in the July 1992 letter will be instructive for your readers. If so, permission for publication is granted."

J.A. Morris

After a slightly more sedate consideration than last time, on 22 April 1993, the reply said:

"We are not inclined to publish your letter because to date there are no data from the United States and Finland that substantiate an increase in Haemophilus disease caused by non-type b strains after vaccination of the population...Incidentally, we were fascinated by your analogy with adenovirus infections after vaccination. Is there documentation of the change in adenovirus types after vaccination? We would very much appreciate receiving the reference for this."

Funny they weren’t "fascinated" the first time...

Dr Morris educated them, and his final paragraph in his reply (21 October 1993) reads:

"Information in the above quoted passages and in the attached references provides a pathway to the fascinating adenovirus vaccine story. That this story is apparently unknown to the editors of PIDJ is the basis for another fascinating story."

In the meantime I had written to the then Minister of Health on 23 March, and 1 May 1993, detailing my concerns and asking key questions, one of which was:

"Will the incidence of other serious infections (black wolves) rise as a result of the demise of HIB (white wolves)?"

In his reply on 3 June 1993, Mr Bill Birch advised me that his advisers had advised him that: "The short answer is that this is unlikely. The papers that you included with your latest letter show that the relative importance of other forms of meningitis increase, but the INCIDENCE remains the same. The only incidence that changes is that of HIB meningitis. And this incidence falls by 90% of its pre- vaccination rate in both of your articles that show figures. So, other causes of meningitis have not filled the gap left by HIB. The white wolves have not been replaced by black wolves to use your analogy. There are just fewer cases of meningitis (wolves) overall, and the reduction in cases is entirely due to a reduction in meningitis due to HIB (white wolves)."

IF A VACCINE is being so useful and NOT affecting any other disease statistics EXCEPT reducing one, surely there should show a REDUCTION in the total number of disease admissions to hospital – NOT the increase noticed over the last few months? Evidently at that time the advisors to Bill Birch
thought we were cruising just nicely.

Another article I came across in the Arch Ped Adol Med Journal Jan 1994, pg. 49 discussed the pre-vaccine Haemophilus decline in all groups but being most dramatic in the unvaccinated under 18 month old group, this way:

"This is consistent with findings from other reports, and it suggests that immunisation is not responsible for all of the falling incidence of Hib disease."

(Refs.: JAMA 1993;269:221 – 226/JAMA 1993;269:227 – 231/JAMA 1993;269:246 –
248.)

But let us not nit-pick. ALL articles said how wonderful the Hib vaccine was. It has been hailed as one of the safest, state-of-the-art vaccines, which is the bench-mark of medical ingenuity.

Let us be generous. Let us say that regardless of the incompleteness of the epidemiological data for America, that the recent claims of making the world a Hib-free planet using a vaccine might even have some basis.

BUT AT WHAT COST?

Is the medical profession assuming that the present increase in pneumonia is just part of swings and roundabouts of disease increase and decrease?

I thought it could be – until I read an article in The Lancet, 11 March 1995, Volume 345, p661, from Finland, the first country to use the Hib vaccine in a widespread fashion.

"INCREASE IN BACTERAEMIC PNEUMOCOCCAL INFECTIONS IN CHILDREN".

TEXT EXTRACTS:

"For comparison, the figure shows the declining occurrence of bacteraemic Haemophilus influenzae type B (Hib) infections in the coverage area of the hospital. Hib vaccinations started in Finland in 1986, and the last case of  invasive disease in our hospital was seen in 1991. Thus our results suggest that following the disappearance of invasive Hib disease in children bacteraemic pneumococcal infections have increased. A similar, although less striking increase has been reported in Philadelphia."

"It is tempting to speculate that the increase in invasive pneumococcal infections is causally related to the disappearance of Hib disease. It is known that Hib vaccinations have reduced the carriage of H influenzae and pneumococci may have found a new niche in colonising children. Even though the reason for the increase in bacteraemic pneumococcal infections remains unknown, the increase is a clinical reality...an increase in systemic pneumococcal infections emphasise the need for effective pneumococcal vaccines for young children."

Now we have a clear link between similar patterns in Kaiser, Philadelphia, Finland and New Zealand. New Zealand statistics show that there has been a gradual increase in pneumococcus ISOLATES (isolates = presence on swabs of pneumococcus – not necessarily disease) since 1990, as there have been with several other nasties. Whether that is because they are LOOKING for it more now than before, or whether that reflects a real increase in disease, is not stated. There had been no media releases reflecting concern about any overall increase in the incidence of CLINICAL PNEUMOCOCCAL DISEASE (as opposed to isolates), which predominantly affects the elderly whose immune systems are weaker. The warning on 26 December 1995 only mentioned babies
and young children.

Why is the difference between ISOLATES and DISEASE important?

The medical literature makes it quite clear, with studies done on healthy people showing that:

"Other organisms will be found in throat swabs. In general these have no relevance to clinical illness, and the laboratory should not report other organisms, including staphylococcus aureus, Haemophilus influenzae, and the meningococcus." (NEW ETHICALS JUNE 1994.)

An even better study in Acta Paediatr 1995; 84:566-4 found that when tracheal and laryngeal aspiration were performed on healthy children it was found the majority carry potentially pathogenic bacteria, and: "we conclude that aspirates from the larynx and the trachea are of limited value in the diagnosis of bacterial PNEUMONIA in children." This would indicate that the carriage and exposure rate of bacterial pneumonia in children is as high as ever. The next logical questions are:

What has happened to make children, instead of just carrying the bacteria, actually come down with the disease?

Two things:

1. Indiscriminate use of paracetemol (See volume 8, No. 3 pgs 3, 4 and 5)
2. On the basis of the above it is my personal opinion that the introduction of the vaccine TETRAMUNE is the prime suspect for the increased number of sick children, either by suppressing the immune system allowing carriage of pneumococcal bacteria to become clinical disease, or by providing a new niche for the bacteria to increase its loading dose in children, resulting in clinical disease. Either way, the result is undesirable.

IS THERE TALK OF A CHILDREN’S VACCINE FOR THIS DREADED NEW THREAT?

ASM News, Vol. 60, No. 1, 1994 sounds concerned because the increase in the number of antibiotic resistant pneumococcal cases is pressing companies for vaccines. There are multivalent vaccines for adults (with very variable effectiveness rates!!!) but a current 23-valent vaccine offers no protection to children less than two years. Merck now has a conjugate vaccine being tested to see if they can prevent otitis media (earache) in children, but the reality is that it is projected to be at least year 2000 before any vaccine is available.

Which brings us back to where we started – the Herald article talking about sicker kids and more of them, and an increase in pneumonia. The first warning signs elsewhere in the world were there to see for those who chose to read – BEFORE they chose to introduce this vaccine to New Zealand.

If the Finland scenario of increasing pneumococcal infections continues here, and invasive pneumococcus disease (or even perhaps other new-niche-seekers) skyrockets in this country, not only will vaccinated children be at risk from pneumococcus, so will unvaccinated children and their parents.

WHY?

Older people who have not had the vaccine are usually immune to Haemophilus (and hopefully pneumococcus) anyway. They developed immunity prior to the age of five in most cases, and most likely our unvaccinated older children have done the same.

If, by using the Hib vaccine, the result is that everyone has to face a new threat in the form of greater carriage of pneumococcal bacteria in vaccinated children then what the medical profession has done, as I stated in my letter to Mr Birch, is SHOOT THE WHITE WOLVES (Hib) and replace them WITH BLACK WOLVES. Pneumococcus is a far more serious disease, and far more untreatable, with more antibiotic resistance than Hib ever had, and the vaccinated majority would be responsible for passing this on to both the unvaccinated minority and the older community. In other words, this vaccine changes the whole existing bacterial balance, and it could be THIS change that has led to more severe sickness overall.

It is, as Dr Morris maintains, repeating the Adenovirus vaccine scenario all over again. Except that the Adenovirus vaccine was removed from use in children and the previous balance in viral types was allowed to re-establish itself.

If the above scenario is true then we, as parents of unvaccinated children, could have every reason to resent the introduction of Hib vaccines. Especially if the solution put forward by medical people is likely to be a pneumococcal vaccine sometime in the future, in addition to the Tetramune.

And if the introduction of a pneumococcal vaccine leads to an increase in something else, what then?

Maybe its time to talk again to Dr John D. Nelson, Editor of THE PEDIATRIC INFECTIOUS DISEASE JOURNAL...I’m sure he will be as enthusiastic as ever to hear from us.

POSTSCRIPT

This article was delayed to see if other countries might voice concerns. The silence has been resounding, which leads to three possible conclusions:

1. Silence is golden

2. It is no longer an issue to them

3. Since there is a pneumococcal vaccine on the horizon, the benefits of the Hib vaccine still outweigh any risks.

I also wonder, on the New Zealand scene whether they even realise or accept the reality of vaccines changing bacterial flora in a community.

 

J Infect. 2004 Nov;49(4):297-301.

Meningitis without a petechial rash in children in the Hib vaccine era.

Makwana N, Nye K, Riordan FA.

Department of Child Health, Birmingham Heartlands Hospital, Bordesley Green East, Birmingham B9 5SS, UK.

AIMS: (1) To determine the causes of meningitis in children immunized with Hib vaccine, presenting without a non-blanching rash; (2) to review the use of dexamethasone in this group. METHOD: Retrospective review of all children with more then 10 white cells/mm(3) in their cerebrospinal fluid (CSF), admitted between January 1998 and August 2002. Children were excluded if they had a non-blanching rash on admission or if their discharge diagnosis was not meningitis. Local guidelines recommended dexamethasone to be given before antibiotics for children with meningitis and no rash. RESULTS: One hundred and eight children were identified. Causes of proven meningitis were: viral 41 (enterovirus 40), bacterial 22. CSF culture or PCR was the only diagnostic test in 31 children. Dexamethasone was given to 16 children. Length of admission was shorter in children with viral compared with bacterial meningitis (4 vs 8 days; P < 0.0001). SUMMARY: Viral meningitis is the commonest cause of meningitis without rash. Enteroviral PCR was the most useful test and needs to be widely available. Confirmation of enteroviral meningitis allowed early discharge. Few children were given dexamethasone, but only 5/108 may have benefited. CONCLUSIONS: The most common cause of meningitis without a rash in British children is enterovirus. The use of dexamethasone in children with meningitis without a rash should be reconsidered or, at least, individualised.

PMID: 15474627 [PubMed - indexed for MEDLINE]

 

Haemophilus b disease after vaccination with Haemophilus b polysaccharide or conjugate vaccine
C. E. Frasch, E. E. Hiner and T. P. Gross
Division of Bacterial Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Md 20892.

The reported frequency of invasive Haemophilus influenzae type b disease occurring within 1 year after immunization was compared in American children who received either Praxis Biologics' Haemophilus b polysaccharide vaccine or Connaught Laboratories' Haemophilus b conjugate vaccine during the first year of distribution. All domestic cases reported to the Food and Drug Administration or the Centers for Disease Control were included in the study. An estimated 4.5 million and 2.0 million doses of polysaccharide and conjugate vaccines were administered, respectively. Approximately three cases of early-onset disease (disease developing less than 15 days after vaccination) per million doses were reported for the polysaccharide compared with four cases per million doses for the conjugate vaccine. There were 30.7 reported vaccine failures per million doses of the polysaccharide vaccine compared with 9.0 per million doses of the conjugate vaccine, a 3.4-fold difference. The reporting rate ratios (cases of vaccine failure to cases of early-onset disease) for the polysaccharide and conjugate were 11.5 and 2.3, respectively, a fivefold difference. Thus, compared with recipients of the polysaccharide vaccine, vaccine failures reported among recipients of the conjugate vaccine were 80% fewer than expected.

Loss of speech after Hib vaccine

http://www.vaccination.org.uk/m/hib23.html

Loss of speech after Hib vaccine

Letter WDDTY April 2001

in 1992, immediately following a then new vaccination against Haemophllus influenzae type b (Hib) infection, my two-year-old granddaughter became unresponsive and regressed until she lost all understanding and speech. She was finally diagnosed with the extremely rare childhood disintegrative disorder Heller’s syndrome.

An Australian National Health and Medical Council information sheet on Hib vaccines advises that Hib meningitis can cause brain damage with later learning difficulties and behavioural disorders (www.health.gov.au). On hearing of US reports of an elevated risk of Hib disease in the week following Hib vaccinations, I sought as much information as possible. Through the US Freedom of Information Act (as WDDTY suggested), I was able to obtain adverse reports for 1988—90, when the vaccine given to my granddaughter was first used in the US. The reports showed clustering of meningitis on day two following vaccination, with an unexpected involvement of the MMR vaccine.

There are 140 serious outcome reports, with 24 cases of meningitis. Five meningitis cases occurred on day two following vaccination and one on day four; nine are classed as ‘no drug effect’ and nine had undefined timing. The ‘no drug effect’ cases must be vaccine failures, occurring at least a month, but up to two and a half years, after vaccination. If the five day-two meningitis cases represent ‘background’ disease, there should have been comparable reports for all seven days of the week following vaccination. It seems most unlikely that ‘background’ disease cases could be so concentrated on day two.

Seven of the 140 serious outcome children also received MMR vaccine, probably representing those who missed this shot at one year of age. Three of these seven children had day-two meningitis. It is most unlikely that the involvement of MMR in day-two meningitis is a chance occurrence. If no one can say which braindamaging illness caused a particular child’s autistic regression, greatest suspicion must fall on the most common illness with features consistent with parents’ experiences.—BG, Canberra

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HIB Vaccine Reactions

Difficulty is that this vaccine is given at the same time as some or all of the following:
DTaP, Polio, Hep B, Prevnar

http://www.vaccination.org.uk/v/hib.html

Vaccine reactions

Haemophilus influenzae (HIB) vaccine reaction citations
HIB vaccination Citations

Basson E, Di Maio M, Stamm D, Cagnin S, Berger C, Floret D. Arch Pediatr 1996 Apr;3(4):342-4 [Haemophilus influenzae meningitis following vaccination. Consequence or coincidence]?[Article in French] Unite de reanimation pediatrique, hopital Edouard-Herriot, Lyon, France. BACKGROUND: The introduction of vaccines against Haemophilus influenzae type b (Hib) has had a substantial impact on Hib infections. Their use has established their excellent safety profiles but occasional adverse effects have been reported.
CASE REPORT: A 4 month-old infant was admitted for a severe form of Hib meningitis with septicemia whose first manifestations developed 3 hours after the first immunization with a conjugate vaccine against Hib (PRP-T). The outcome was good without any sequelae.
DISCUSSION: A dramatic decrease in serum antibodies due to antigen-antibody reaction during the first days after immunization has been reported; this mechanism and some epidemiological data could favor the hypothesis that the vaccine is responsible for the infection, at least the unconjugated vaccines.
CONCLUSION: Any fever occurring in the immediate post-immunization period must alert the possibility of a Hib infection.

D'Cruz OF, Shapiro ED, Spiegelman KN, Leicher CR, Breningstall GN, Khatri BO, Dobyns WB. Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome) after immunization with Haemophilus influenzae type b conjugate vaccine. J Pediatr. 1989 Nov;115(5 Pt 1):743-6. Noabstract available. PMID: 2809907 [PubMed - indexed for MEDLINE] Ferson MJ, Fisher GT. Antigenuria following Haemophilus influenzae type B
vaccination. J Paediatr Child Health. 1993 Dec;29(6):482-3. No abstract available. PMID: 8286173 [PubMed - indexed for MEDLINE]

Granoff et al. (1986) analysed 228 reports of invasive disease due to Hib in vaccinated children submitted to the FDA administration between May 1985and September 1987. Over 90% of these children were more than 24 months of age, when the vaccine is supposed to be somewhat effective

Gervaix A, Caflisch M, Suter S, Haenggeli CA. Guillain-Barre syndrome following immunisation with Haemophilus influenzae type b conjugate vaccine. Eur J Pediatr. 1993 Jul;152(7):613-4. PMID: 8354324 [PubMed - indexed for MEDLINE]

Granoff DM, et al.Host and bacterial factors associated with Haemophilus influenzae type b disease in Minnesota children vaccinated with type b polysaccharide vaccine. J Infect Dis. 1989 May;159(5):908-16. PMID:2785147; UI: 89215362
Host and bacterial factors were evaluated among 86 Minnesota children with Haemophilus influenzae type b disease detected by active surveillance after introduction of type b polysaccharide vaccine in the state. Children were 2-6 y of age. Thirty-three (38%) had been vaccinated. There was no significant difference between the frequency of low serum concentrations of IgM, IgA, IgG, or IgG2 in the vaccinated and nonvaccinated subjects (13%vs. 8%, P = .5). The presence of the Gm immunoglobulin allotype phenotype (1,3,17;23;5,13,21), previously associated with a lower relative risk of vaccine failure in children from other states, was associated with a fourfold decrease in the relative risk of vaccine failure in Minnesota (Pless than .07). Haemophilus isolates from 58 of the children were available for clonal characterization by multilocus electrophoresis and outer membrane protein subtyping. There were no significant differences between the clone distribution of the strains causing disease in vaccinated and nonvaccinated patients, and nearly all disease-producing clones in Minnesota also are known to cause disease in other areas of the country. Thus, vaccine failure in Minnesota is infrequently associated with hypogammaglobulinemia or with infection by unusual clones of a H. influenzae type b. Also, the Gm phenotype associated with protection against vaccine failure in other areas of the USA appears to be protective in Minnesota. PMID: 2785147, UI: 89215362

Granoff et al. (1986)] deals with 55 cases of invasive Hib diseases occurring in Children at least three weeks after vaccination. Meningitis developed in 39 children of whom 3 died and 6 had neurologic after-effects. The level of antibody to Hib in convalescent-phase serum from 31 of the vaccinated children who had Hib disease was significantly lower than that in the serum from 25 patients of similar age (range 17 to 47 months) with the disease who had never received the Hib vaccine.

"Risk factors for invasive Haemophilus influenzae disease among children 2-16 years of age in the vaccine era, Switzerland, 1991-1993" (International Journal of Epidemiology, vol. 25, no. 6, December 1996, pp. 1280-5): "Continued surveillance, and detailed investigation of direct and indirect effects of conjugated vaccines and risk factors…are important." 143 cases with invasive disease were selected, and vaccination status ascertained. "Cases more often than controls reported suffering from asthma and allergies… The observed association between asthma and epiglottitis is novel and deserves further investigation."

Moral Gil L, Gonzalez Montero R, Rubio Calduch EM, Moya Benavent M. [Type b Haemophilus influenzae meningitis after 2 doses of conjugated vaccine] An
Esp Pediatr. 1996 Dec;45(6):645-6. Spanish. No abstract available.PMID: 9133234 [PubMed - indexed for MEDLINE]

Nejmi SE, Tajri M, Laraki M, Sadraoui A. [Guillain-Barre syndrome following immunization against Haemophilus influenzae type b] Arch Pediatr. 2001Aug;8(8):894-5. French. No abstract available. PMID: 11524923 [PubMed -indexed for MEDLINE]

Schreurs AJ, Nijkamp FP. Bronchial hyperreactivity to histamine induced by Haemophilus influenzae vaccination. Bronchial hyperreactivity to histamine 4 days following vaccination with the human respiratory pathogen Haemophilus influenzae was tested in two in vivo and one in vitro models. Conscious vaccinated guinea pigs exposed to aerosolized histamine became asphyxial significantly faster than saline-treated controls. Also the bronchoconstriction in anaesthetized
guinea pigs as a result of i.v. histamine was significantly potentiated in the H. influenzae pretreated group. Isoprenaline (30 micrograms/kg) partially inhibited the bronchoconstriction. The difference in histamine sensitivity between the two groups however remained. Protection against bronchoconstriction by atropine on the other hand was significantly enhanced in the vaccinated animals. This suggests a hyperreactivity of the parasympathetic, cholinergic pathways as a result of H. influenzae vaccination. PMID: 6335351, UI: 85118726

Terpstra GK, Raaijmakers JA, Hamelink M, Kreukniet J. Effects of Haemophilus influenzae vaccination on the (para-)sympathic-cyclic nucleotide-histamine axis in rats.Ann Allergy 1979 Jan;42(1):36-40 To determine whether Haemophilus influenzae could be a factor in human atopy its effects were studied on the (para-)Sympathic Cyclic nucleotide-histamine axis in rats. Haemophilus influenzae vaccination induced changes in the cholinergic system compatible with higher cyclic GMP levels and enhanced histamine release. The authors suggest an involvement of the cholinergic system in Haemophilus influenzae vaccination effects.
PMID: 216288, UI: 79101862

Wiersbitzky S, et al. [Encephalitis after simultaneous DPT and oral trivalent poliomyelitis (Sabin vaccine) and HiB preventive vaccination]? Kinderarztl Prax. 1993 Jun;61(4-5):172-3. German. No abstract available.PMID: 8103131; UI: 93368099. Milstien JB, et al. Adverse reactions reported following receipt of aemophilus influenzae type b vaccine: an analysis after 1 year of  marketing. Pediatrics. 1987 Aug;80(2):270-4. PMID: 3497381; UI: 87288854.


Citations below taken from: Can Hib Vaccine Cause Asthma?----- Heidi White

Muhlemann K; Alexander ER; Weiss NS; Pepe M; Schopfer KRisk factors for invasive Haemophilus influenzae disease among children 2-16 years of age in the vaccine era, Switzerland 1991-1993. The Swiss H. Influenzae Study Group. Int J Epidemiol 1996 Dec;25(6):1280-5 PMID: 9027536 UI: 97179250 ABSTRACT: BACKGROUND: Continued surveillance, and detailed investigation of direct and indirect effects of conjugated vaccines and risk factors for invasive H.influenzae serotype B (Hib) disease in the vaccine era are important. METHODS: 143 cases with invasive disease between 1991 and 1993 aged 2-16 years were selected retrospectively from a large incidence trend study. Controls (n = 336) were recruited from local vital registries and matched to cases for age, gender, and residence. Hib vaccination histories mong study subjects and their siblings and other sociodemographic variables were obtained by questionnaires completed by the parents of these children. Adjusted odds ratio (OR) estimates were calculated by conditional logistic regression analysis. RESULTS: Most vaccinated subjects had received the Polysaccharide- Diphtheria Toxoid vaccine and estimated vaccine efficacy was high (95%; 95% confidence interval [CI] 60-99%). Also, the results suggested that protection afforded by vaccination against Hib extended to the family members of vaccinated children. School attendance was found to be protective against invasive Hib disease (OR:0.33; CI:1.2-14.4). Cases more often than controls reported suffering from asthma and allergies (OR:4.8; CI:1.2-19.4). CONCLUSIONS: Post-licensure vaccine efficacy is high among children > or = 2 years of age. The observed association between asthma and epiglottitis is novel and deserves further investigation.

Kurono Y; Yamamoto M; Fujihashi K; Kodama S; Suzuki M; Mogi G; McGhee JR; Kiyono H Nasal immunization induces Haemophilus influenzae-specific Th1
and Th2 responses with mucosal IgA and systemic IgG antibodies for protective immunity. J Infect Dis 1999 Jul;180(1):122-32 PMID: 10353870 UI: 99282596
ABSTRACT: To determine the efficacy of a mucosal vaccine against nontypeable Haemophilus influenzae (NTHi), mice were immunized nasally, orally, intratracheally, or intraperitoneally with NTHi antigen together with cholera toxin. Antigen-specific IgA antibody titers in nasal washes and the numbers of antigen-specific IgA-producing cells in nasal passages showed the greatest increases in mice immunized nasally. Cytokine analysis showed that interferon-gamma, interleukin (IL)-2, IL-5, IL-6, and IL-10 were induced by nasal immunization, suggesting that Th2- and Th1-type cells were generated. Furthermore, bacterial clearance of a homologous strain of NTHi from the nasal tract was significantly enhanced in the nasal immunization group. These findings suggest that nasal immunization is an effective vaccination regimen for the induction of antigen-specific mucosal immune responses, which reduce the colonization of NTHi in the nasal tract.

Nijkamp FP, et al. Facilitation of histamine release in the Haemophilus influenzae vaccinated experimental animal. Br J Pharmacol. 1980 Jan;68(1):147P. No abstract available. PMID: 6153543 UI: 80131284

Raaijmakers JA; Terpstra GK; Kreukniet J Mast cells as a possible source of Haemophilus influenzae-induced changes in plasma and lung histamine levels. Int Arch Allergy Appl Immunol 1980;61(3):352-7 PMID: 6153378 UI: 80114589 ABSTRACT: Histidine decarboxylase activity and histamine levels of peritoneal mast cells were enhanced 4 days after intraperitoneal Haemophilus influenzae vaccination of rats. Incubation of the cells with propranolol (3.4 x 10(-4) M) resulted in histamine release and an increased histidine decarboxylase activity. Histidine decarboxylase activity and histamine release were more increased in the presence of propranolol in mast cells obtained from H. influenzae-vaccinated rats. An increased mediator release is also suggested by the increase of the number of
peritoneal eosinophils. These data might explain the earlier observed enhanced plasma and lung histamine levels in H. influenzae- vaccinated rats.

Terpstra GK; Raaijmakers JA; Kreukniet J Comparison of vaccination of mice and rats with Haemophilus influenzae and Bordetella pertussis as models of atopy. Clin Exp Pharmacol Physiol 1979 Mar-Apr;6(2):139-49 PMID: 311260UI: 79126330
ABSTRACT: 1. Rats and mice were vaccinated with Haemophilus influenzae in different vaccination schedules whereafter blood eosinophils were counted. In rats a single vaccination resulted in a dose-dependent effect on the blood eosinophil count in a pattern comparable with that after Bordetella pertussis vaccination. In a long-term vaccination schedule (five times a week for 5 weeks) rats developed a constant eosinophilia. In mice a single vaccination resulted in an eosinopenia of a consistent pattern which differed from the response after Bordetella pertussis vaccination; in a long-term vaccination schedule, eosinophilia was evoked for a period of about 13 days. 2. Thirty minutes after an adrenaline injection in vaccinated rats and mice with Haemophilus influenzae, hyperglycaemic and eosinophilic responses were measured. The eosinophilic response after adrenaline was inhibited in both species; the hyperglycaemic response in rats was unaltered, in mice the response was slightly but significantly (P less than 0.05) decreased. 3. The sensitivity to several drugs was tested
in mice, 5 days after vaccination with Haemophilus influenzae or Bordetella pertussis. Haemophilus influenzae vaccination reduced the isoprenaline sensitivity and increased the noradrenaline sensitivity. Bordetella pertussis vaccination reduced the isoprenaline sensitivity while the sensitivity to histamine and adrenaline was raised. 4. The Haemophilus influenzae vaccinated experimental animal provides a model that is possibly more related to human atopy than the Bordetella pertussis vaccinated animal.

Terpstra GK; Raaijmakers JA; Hamelink M; Kreukniet JEffects of Haemophilus influenzae vaccination on the (para-)sympathic- cyclic nucleotide-histamine axis in rats. Ann Allergy 1979 Jan;42(1):36-40 PMID: 216288 UI: 79101862 ABSTRACT: To determine whether Haemophilus influenzae could be a factor in human atopy its effects were studied on the (para-)Sympathic Cyclic nucleotide-histamine axis in rats. Haemophilus influenzae vaccination induced changes in the cholinergic system compatible with higher cyclic GMP levels and enhanced histamine release. The authors suggest an involvement of the cholinergic system in Haemophilus influenzae vaccination effects.

Schreurs AJ; Nijkamp FP Bronchial hyper-reactivity to histamine induced by Haemophilus influenzae vaccination. Agents Actions 1984 Oct;15(3-4):211-5 PMID: 6335351 UI: 85118726 ABSTRACT: Bronchial hyper-reactivity to histamine 4 days following vaccination with the human respiratory pathogen Haemophilus influenzae was tested in two in vivo and one in vitro models. Conscious vaccinated guinea pigs exposed to aerosolized histamine became asphyxial significantly faster than saline-treated controls. Also the bronchoconstriction in anaesthetized guinea pigs as a result of i.v. histamine was significantly potentiated in the H. influenzae pretreated group. Isoprenaline (30 micrograms/kg) partially inhibited the bronchoconstriction. The difference in histamine sensitivity between the two groups however remained. Protection against bronchoconstriction by atropine on the other hand was significantly enhanced in the vaccinated animals. This suggests a hyper-reactivity of the parasympathetic, cholinergic pathways as a result of H. influenzae vaccination.

Terpstra GK; Kreukniet J; Raaijmakers JA Changes in beta-adrenergic responses as a consequence of infection with micro-organisms. Eur J Respir Dis Suppl 1984;135:34-46 PMID: 6329808 UI: 84236583 ABSTRACT: The B. pertussis model of atopy as proposed by Szentivanyi in 1968 has been a starting point for much research involving the pathogenesis of COLD. Moreover, it supplied more insight into the pharmaco-therapeutic approach toward this group of diseases. In this review, it is shown that products of bacteria considered to be a constituent of the normal flora of the human upper respiratory tract, such as H. influenzae, elicit changes in adrenoceptor responsiveness which are compatible with an enhanced tendency toward bronchoconstriction. One of the features of human atopy is enhanced mediator release after appropriate stimuli resulting in bronchoconstriction. This phenomenon can be mimicked in an animal model, the H. influenzae-vaccinated rat or guinea pig; enhanced histamine synthesis and release are found in vivo as well as in vitro. The effects point in the direction of a beta-adrenergic defect which is not only demonstrable in biochemical but also in physiologically oriented parameters. Pulmonary smooth muscle tissue appears to be less responsive to beta-adrenergic agonists and has an enhanced tendency to contract. The view that these changes are indeed the reflection of changes in adrenoceptor systems has been investigated in guinea pigs and rats. In both species impairment of beta-adrenergic systems together with a reduction in the
number of beta 2-adrenoceptors was found after vaccination. Also the involvement of other factors, e.g., catecholamines, has been demonstrated. Comparable changes occur within the pulmonary adrenoceptor populations of COLD patients, suggesting disturbed homeostasis in the autonomic nervous system, possibly leading to bronchoconstriction. The question whether a bacterial factor is important in these changes and might induce, sustain or enhance the effects of other factors or even have a role in the pathogenesis of COLD is discussed in this review.

Schreurs AJ; Terpstra GK; Raaijmakers JA; Nijkamp FP The effects of Haemophilus influenzae vaccination on anaphylactic mediator release and isoprenaline-induced inhibition of mediator release. Eur J Pharmacol 1980 Apr 4;62(4):261-8 PMID: 6154589 UI: 80178911 ABSTRACT: The influence of Haemophilus influenzae on anaphylactic mediator release from ovalbumin-sensitized isolated guinea pig lungs wasinvestigated. Lungs from H. influenzae-vaccinated animals released prostaglandins and thromboxanes following a smaller dose of ovalbumin than was effective in non-vaccinated animals. Histamine release was significantly increased in 4 day-vaccinated animals but not 1 or 10 days after vaccination, while bronchoconstriction was potentiated in 1 and in 4 day-vaccinated animals. This increased histamine release was achieved following 2 micrograms ovalbumin. In contrast, doses of 10 micrograms and 1mg ovalbumin respectively did not affect and decreased histamine release in the vaccinated group. The inhibition of anaphylactic mediator release by an infusion of 6 x 10(-9) M isoprenaline was significantly attenuated by H. influenzae vaccination. These results indicate an increased sensitivity to antigenic challenge and suggest that the functioning of beta-adrenoceptors was decreased as a result of H. influenzae vaccination.

Schreurs AJ; Versteeg DH; Nijkamp FP Involvement of catecholamines in Haemophilus influenzae induced decrease of beta-adrenoceptor function.
Naunyn Schmiedebergs Arch Pharmacol 1982 Sep;320(3):235-9 PMID: 6290901
UI: 83037012
ABSTRACT: The deeper airways of patients with asthmatic bronchitis are often infected with Haemophilus influenzae. Vaccination of guinea pigs with H. influenzae resulted in a significant impairment of the isoproterenol induced relaxation of isolated tracheal spirals by approximately 50% 4 days following vaccination. In the present study we further investigated the effects of some drugs affecting catecholamine release on the H. influenzae induced functional desensitization of tracheal spirals. Benserazide, an inhibitor of dopa-decarboxylase, completely prevented the reduction in isoproterenol-induced relaxation after H. influenzae vaccination, while no effect on relaxation of tracheal spirals from control animals was detected. On the other hand, inhibiting the re-uptake of catecholamines with desipramine did not influence the relaxation in the H. influenzae vaccinated tracheal spirals. Treatment of control animals with desipramine
however resulted in a decreased relaxation of the isolated spirals by 40%. One day following vaccination with H. influenzae the level of norepinephrine in lung tissue was significantly elevated by 71%, and in plasma by 77%, while after 4 days no significant effects were observed. The spontaneous release of norepinephrine, epinephrine and dopamine of tracheal incubates was increased at days 1 and 4 following vaccination. The release of catecholamines from minced lung incubates of H. influenzae pretreated guinea pigs did not differ from that of controls. On the basis of these results it may be suggested that catecholamine metabolism is changed in lungs from H. influenzae vaccinated animals. Catecholamines, accordingly may play a role in the desensitization of beta-adrenoceptors by H. influenzae.

Schreurs AJ; Terpstra GK; Raaijmakers JA; Nijkamp FP Effects of vaccination with Haemophilus influenzae on adrenoceptor function of tracheal and
parenchymal strips. J Pharmacol Exp Ther 1980 Dec;215(3):691-6 PMID:
6969303 UI: 81071818
ABSTRACT: Haemophilus influenzae is a bacterium that can be isolated from the deeper airways of asthmatic patients. We investigated the effect of vaccination with H. influenzae on alpha and beta adrenoceptor function in guinea-pig tracheal spirals and lung parenchymal strips. The tracheal spirals from H. influenzae-vaccinated animals showed significantly less relaxation to isoproterenol as compared to controls, independent of whether the trachea was maximally contracted with carbachol or only exhibited an intrinsic tone. Furthermore, an increased contractile response to carbachol was observed in these spirals. To isoproterenol in the presence of a beta-2 adrenergic antagonist (H35/25), or to albutamol alone, the tracheal preparations from H. influenzae-vaccinated animals also showed a decreased relaxation. These results suggest involvement of both beta-1 and beta-2subtype adrenoceptors. On the other hand, lung parenchymal strips from vaccinated guinea-pigs relaxed significntly more to these drugs. This effect was not influenced by H35/25 but could be inhibited by
phenoxybenzamine. Histamine-induced contraction did not differ between the groups. These results indicated that H. influenzae causes a partial blockade of the beta adrenoceptors in tracheal spirals and, therefore, may have important implications in asthmatic bronchitis. In contrast, parenchymal lung strips of the H. influenzae-pretreated group showed an increased relaxation.

Nijkamp FP, et al. Inhibition of effects of isoprenaline and adrenaline by Haemophilus influenzae vaccination. Br J Pharmacol. 1980 Jan;68(1):146P.
No abstract available. PMID: 6965598

Schreurs AJ; Verhoef J; Nijkamp FPBacterial cell wall components decrease the number of guinea-pig lung beta-adrenoceptors. Eur J Pharmacol 1983 Jan
28;87(1):127-32 PMID: 6301848 UI: 83182671 ABSTRACT: Infections of the deeper respiratory airways can contribute to the progression of chronic asthmatic bronchitis. In the present report a number of microorganisms affecting the number of beta-adrenoceptors in guinea-pig lung homogenates are described. Haemophilus influenzae, Streptococcus pneumoniae, Bordetella pertussis and Escherichia coli O111B4 induced a significant decrease of the number of beta- adrenoceptors (by approximately 20%). Staphylococcus aureus, influenza A virus and Escherichia coli J5 were not active. These data point to a common factor
shared by gram-negative bacilli; i.e. endotoxin. Purified endotoxin of E. coli O111B4 also decreased the number of beta- adrenoceptors, while E. coli J5-LPS did not. This suggests that neutral polysaccharides of bacterial cell walls, especially those in the 'O'- antigenic side chain of gram-negative endotoxins may be responsible for the decrease of beta-adrenoceptor number and therefore contribute to the pathogenesis of chronic asthmatic bronchitis. Intact endotoxin seems to be necessary since neither the isolated lipid nor the polysaccharide part of E. coli O111B4 LPS affected the number of beta- adrenoceptors in the lung.

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More adverse reactions after vax

http://www.nccn.net/~wwithin/hib.htm

Guillain-Barre syndrome following immunisation with Haemophilus influenzae
type b conjugate vaccine.

Safety evaluation of PRP-D Haemophilus influenzae type b conjugate vaccine in children immunized at 18 months of age and older: follow-up study of 30,000 children."Hospitalization and seizures (0.15% and 0.09% of vaccinated children, respectively) occurring within 1 month of immunization appeared to be unrelated to vaccination. One 29-month-old child had onset of a fatal episode of Hib sepsis/meningitis within 48 hours of vaccination. Also, a 30-month-old child developed Hib meningitis 10 months after PRP-D vaccination. "

Post immunization Hib antigen detection in the CSF of a patient with meningococcal meningitis.

The effects of Haemophilus influenzae vaccination on anaphylactic mediator release and isoprenaline-induced inhibition of mediator release.

Effects of Haemophilus influenzae vaccination on the (para-)sympathic-cyclic nucleotide-histamine axis in rats

Bronchial hyperreactivity to histamine induced by Haemophilus influenzae vaccination.

IgA nephropathy in mice following repeated administration of conjugated
Haemophilus influenzae type B vaccine (PRP-T).

Mortality and morbidity from invasive bacterial infections during a
clinical trial of acellular pertussis vaccines in Sweden

http://users.adelphia.net/~cdc/VaccineInfo.htm#HiB
May be some duplicates
Spectrum of disease due to Haemophilus influenzae type b occurring in
vaccinated children.

A high degree of natural immunologic priming to the capsular polysaccharide may not prevent Haemophilus influenzae type b meningitis.

The effects of Haemophilus influenzae vaccination on anaphylactic mediator release and isoprenaline-induced inhibition of mediator release.

Hemophilus influenzae meningitis despite vaccination

Disease caused by Haemophilus influenzae type b in the immediate period after homologous immunization: immunologic investigation.

Association between type 1 diabetes and Hib vaccine.

Immunologic memory in Haemophilus influenzae type b conjugate vaccine failure.

Limited efficacy of a Haemophilus influenzae type b conjugate vaccine in Alaska Native infants. The Alaska H. influenzae Vaccine Study Group

Impaired antibody response to Haemophilus influenzae type b polysaccharide and low IgG2 and IgG4 concentrations in Apache children

Safety, tolerability and immunogenicity of a Haemophilus influenzae type b vaccine containing aluminum phosphate adjuvant administered at 2, 3 and 4 months of age.

Post-marketing evaluation of the short term safety of COMVAX®

Vaccinations may induce diabetes-related autoantibodies in one-year-old children.

Blue Cellulitis: A Rare Entity In The Era Of HIB Conjugate Vaccine.

Outbreak of Haemophilus influenzae type b disease among fully vaccinated
children in a day-care center

Endotoxin Content in Haemophilus influenzae Type b Vaccine

Natural immunity to Haemophilus influenzae type B in children of Ankara,
Turkey

Cellulitis resulting from infection by Haemophilus influenzae type b:
report of two cases

Meningitis without a petechial rash in children in the Hib vaccine era

Vaccination failure: case report of Haemophilus influenzae b meningitis in a 14-month-old child

Comparison of vaccination of mice and rats with Haemophilus influenzae and Bordetella pertussis as models of atopy

Effects of Haemophilus influenzae vaccination on the (para-)sympathic-cyclic nucleotide-histamine axis in rats

Bronchial hyperreactivity to histamine induced by Haemophilus influenzae