2009 H1N1: vaccine safety

From Medscape Infectious Diseases
2009 H1N1: What's New This Week -- December 7, 2009
Commentary by John G. Bartlett, MD
John G. Bartlett, MD

Posted: 12/09/2009

Safety of Influenza A (H1N1) 2009 Monovalent Vaccines
The CDC reports a review of swine flu vaccine safety data.[1] The methods summarized in this report are (1) the US Vaccine Adverse Event Reporting System (VAERS), with 3783 reports, and (2) data from the Vaccine Safety Datalink (VSD) for 438,376 patients in managed care organizations who received vaccines.

VAERS data. Through November 24, VAERS received 3783 reports of adverse events following H1N1 vaccination.

Serious reactions were reported in 204 of 46.2 million doses of H1N1 vaccines distributed. Table 1 indicates how swine flu reports compare with reports received from seasonal flu vaccine.
Table 1. Reported Reactions to Swine Flu: Vaccine vs Seasonal Flu Vaccine

Any Reaction Serious Reaction
Swine flu vaccine
Seasonal flu vaccine 82/million doses
47/million doses 4.4/million doses
2.9/million doses

Deaths: 13 reported to VAERS, including 3 after live virus vaccine. Nine of the 13 were associated with a serious underlying disease, 1 was a car crash, and 3 are under review.
Guillain-Barré syndrome: 12 possible cases identified: 4 confirmed, 4 not confirmed, and 4 under review.
Anaphylaxis: 19 possible anaphylaxis cases; 13 of these 19 have been confirmed.

VSD data review. As of November 21, 2009, 438,376 doses of H1N1 vaccine had been administered, including 323,345 injectable and 115,031 nasal spray.
During October 1-November 21, no cases of Guillain-Barré syndrome and only 1 case of anaphylaxis had been detected.

The increase in adverse event reports for swine flu vaccine over seasonal flu vaccine may represent efforts to enhance reporting. VSD has the ability to confirm signals from VAERS, but so far these show no increases above the background rates for monitored health events among recipients of H1N1 vaccines.

Commentary. There is considerable concern about the safety of the H1N1 vaccine, presumably because it is new and it was developed relatively quickly.

Patients need to know:

It is manufactured by the same methods used for all flu vaccines for the past 40 years. This vaccine has a different flu antigen, but the flu antigen in the vaccine changes nearly every year.
There is no adjuvant in this vaccine. Many people are concerned about the presence of an adjuvant.
Our experience with 438,000 doses is that no safety concerns have been identified to date.
An extensive series of studies monitors safety of the vaccine. The ones summarized here, VAERS and VSD, are only 2 of 11 safety monitoring surveillance systems.

Australia's Winter With Pandemic Influenza H1N1
The Australian experience[2] with swine flu is of interest because the pandemic hit simultaneously with seasonal flu (which might be expected to occur in the United States in the next 4 months), and Australia had careful planning and record keeping instated. The following are highlights:

The first wave of influenza hit in mid-May 2009 and lasted 18 weeks.
The pandemic strain of influenza A (H1N1) accounted for 90% of influenza isolates by week 8.
School absenteeism was the same as it was in 2007, which was Australia's worst influenza season.
13% of hospitalized patients were admitted to the ICU.
The highest rate of hospitalization was in children younger than 5 years old.
A relatively large number of "lung only" single organ failure patients received ECMO and two thirds survived.
A distinguishing feature was the young age of hospitalized patients -- the median age was 43 years. The median age of patients who died was 53 years compared with 83 years in previous flu seasons.

Commentary. The clinical features reported here are "old news." Most interesting is the dominance of swine flu H1N1 over seasonal flu strains and the relevance of this to influenza in the northern hemisphere. But we can't be certain that our experience will be like Australia's because we have already experienced 2 waves and many vaccinations have been given that may have created "herd immunity" to modify the distribution of strains in the influenza season.

For practical purposes, here is the bottom line:

The recommended vaccine strategy is easy:
Patients should get both vaccines if available and according to priority. A history of confirmed swine flu means that the patient should receive the seasonal flu vaccine only.
Prescribing antiviral agents will be challenging for practitioners because decisions must take into consideration the viral strain as well as epidemiologic patterns of sensitivity.
We know that the right drug should be given as quickly as possible and we also know that we often won't know the strain. The current sensitivity patterns are described in Table 2.

Table 2. Sensitivity Patterns

Oseltamivr Zanamivr Rimantadine
Swine flu A (H1N1) Sensitive Sensitive Resistant
Seasonal flu A (H1N1) Resistant Sensitive Sensitive
Seasonal flu A (H3N2) Sensitive Sensitive Resistant
Seasonal flu (type B) Sensitive Sensitive Resistant


The challenge will be simultaneous seasonal and pandemic H1N1 strains because they show opposite sensitivities to oseltamivir and rimantadine.
So far, these 2 strains have not surfaced together since pandemic H1N1 took over.

When to Consider the Use of Antibiotics in the Treatment of 2009 H1N1 Influenza-Associated Pneumonia
A difficulty arises when a patient has influenza or influenza with a bacterial superinfection that requires antibiotics.[3] A recent report showed that bacterial pathogens, including Staphylococcus aureus, were present in 17/53 (32%) of fatal cases of novel H1N1 infection, including 8 in children.[4] Table 3 summarizes the clinical features of influenza vs influenza with a bacterial superinfection.

Table 3. Detection of Agents of Pneumonia: Influenza vs Influenza + Bacterial Pathogen

Indicator Influenza Influenza + Bacterial Pathogen
Influenza identified Usually found Often found less because later in disease course
Fever Usually found Usually found after a period of defervescence
Respiratory specimen culture Normal flora Pathogen: usually S pneumoniae, S aureus or Group A strep
X-ray Diffuse Lobar consolidation
Onset of respiratory compromise Early: 1-2 days Later: 4-7 days


In regard to antimicrobial selection, these experts recommend coverage for methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae using a second- or third-generation cephalosporin with the addition of MRSA coverage if there is evidence of necrotizing pneumonia or if a Gram stain or culture of respiratory secretions suggests this pathogen. For outpatients, they suggest amoxicillin-clavulanate or a second- or third-generation cephalosporin.

Commentary. The clinical features suggesting bacterial superinfection are reminders of the well-known report of the 1957-1958 pandemic from NY Hospital-Cornell,[5] when the classic biphasic pattern with typical flu symptoms -- improvement and then rapid deterioration with lobar pneumonia -- was described. The main pathogens then and now are S pneumoniae, S aureus, and group A streptococci. The antibiotics preferred for hospitalized patients with suspected S pneumoniae would be cefotaxime or ceftriaxone. For S aureus (either MRSA or untested), the preference would be for vancomycin dosed to trough levels of 15-20 µg/mL or linezolid (which appears to have better lung penetration).

H1N1 Flu Still Down but 198 Children Dead
H1N1 remains at epidemic levels but is below its peak from October 2009. The Centers for Disease Control and Prevention estimates that more than 22 million Americans have been infected with H1N1 and 3900 have died. Since March 2009, 198 children in the United States have died from H1N1, many from associated bacterial infections.

Commentary. The question that I am asked most frequently is, "The swine flu vaccine is now pretty easy to get, but the cases are down; do I need to get vaccinated?" The answer: "Yes, cases are down, for the second wave that was predicted when school started. There may be a third wave that corresponds to seasonal flu, so you still need to get vaccinated."

Australia had seasonal flu and swine flu occur together because it is in the southern hemisphere. Swine flu H1N1 pushed out seasonal flu and was the dominant flu virus during their winter season. That is likely to happen here, but this is a guess. If it does, this is the window of opportunity to get vaccinated.
Tell patients to get both the swine flu vaccine and seasonal flu vaccine because they are complementary, reminding them that seasonal flu vaccine will not prevent swine flu and vice versa.

One additional point: Many patients tell me that they think they already had swine flu and do not need the vaccine. Only 20%-35% of people who have had flu-like illnesses during the second wave of influenza actually had positive tests for swine flu when they were tested. This means that 65%-80% had something else -- probably paraflu, RSV, adenovirus, rhinovirus, etc.
If they had a confirmed H1N1 test between April and December 2009, they only need to get the seasonal flu vaccine.
If they did not have a confirmed test, then they should be considered for both vaccines.
Note that these vaccines can be given at the same visit but are given at different injection sites.

H1N1 Epidemic Update
During influenza week 47 (November 22-28, 2009), influenza activity continued to decrease in the United States.[4] More than 99% of strains that were subtyped were 2009 influenza A (H1N1).

Commentary

Virtually all influenza at this time is swine flu. Seasonal flu has not started.
The number of outpatient visits for influenza-like illnesses is 3.7%, which is above the national baseline of 2.3% but lower than earlier reports. Hospitalizations and deaths due to influenza are down.

Conclusion: The second wave is subsiding, but there is still widespread illness in 25 states.
Resistance testing shows that 15 of 1540 (less than 1%) 2009 H1N1 strains were resistant to oseltamivir. Nearly all 15 had previous exposure to oseltamivir.
Conclusion: Oseltamivir is still active against nearly all strains, especially in patients who have not had oseltamivir exposure.

Pediatric deaths attributed to this influenza strain in the United States now total 198, including 34 in children younger than 2 years of age. Of these, 89 had cultures of normally sterile sites and 28/89 (31%) showed bacterial superinfections involving a predictable menu of pathogens.

Conclusion: There is increasing concern and attention on bacterial superinfections. Clues are (1) biphasic course, (2) elevated WBC, (3) x-ray showing lobar consolidation, and (4) sputum showing the likely pathogens: pneumococcus, Staphylococcus aureus, or Group A streptococcus.