The current state of influenza vaccination and treatment

If the H1N1 pandemic had one positive side effect, it may be the increased attention now being paid to seasonal and other strains of influenza by both the public and the medical community. Influenza vaccination and treatment are being evaluated in hundreds of scientific studies concurrently, and the body of knowledge about influenza grows daily. Several experts highlighted this research in discussions with Infectious Diseases in Children, laying out some of the most current scientific findings on influenza vaccination and treatment.

Flu vaccines: present and future

In her presentation at the recent Infectious Diseases in Children Symposium in New York, Infectious Diseases in Children Editorial Board member Kathryn M. Edwards, MD, delineated the available vaccines against current circulating strains of influenza and highlighted possible approaches for future vaccines.

Edwards cited a 2001 study conducted with her colleague Kathleen Neuzil, in which trivalent inactivated influenza vaccine was 91% effective in preventing culture positive H1N1 influenza and 77% effective in preventing culture-positive H3N2 in children. Efficacy rates increased with age, with those aged 6 to 15 years faring somewhat better than those 1 to 5 years of age. Vaccine efficacy varies with the match of the vaccine and the circulating influenza strains, with higher efficacy when the match is good.

“A new influenza vaccine is manufactured each year. Sometimes the vaccine strains match the circulating strains and sometimes they do not,”

Edwards told Infectious Diseases in Children in an interview. “To this day, finding out which strains to include in the vaccine is problematic. In spite of increasing knowledge about the influenza virus, we still have great difficulty predicting which influenza strains will be circulating.”

Most recently, a 2007 study in The New England Journal of Medicine compared the live trivalent influenza spray vaccine with the inactivated trivalent vaccine in young children with a mean age of 26 months.

“Nearly 8,000 children were enrolled in the study. The live influenza spray vaccine was more effective than the inactivated influenza injection, with only about half as much as confirmed influenza in children who received the spray rather than the shot,” Edwards said.

One of the theories behind the differing efficacy between the two vaccines in children is that children respond better to the live vaccines because they have less antibody to influenza in the nose, where the vaccine is given, than adults.

“The live virus grows better in the noses of young children. Adults have built up antibodies in their noses, so the live vaccine doesn’t grow as well and does not induce as much protection,” Edwards said.

Despite the improved efficacy in children, not all children should get the nasal spray vaccine, she said. The spray is not FDA approved in children younger than 2 years. The same The New England Journal of Medicine study found that children aged 6 to 11 months given the live vaccine spray were significantly more likely to be hospitalized than children who received the inactivated vaccine, regardless of the presence of wheezing (P=.002).

Because the live vaccine can trigger wheezing episodes, it should not be given to patients with asthma. Patients with immune problems or underlying disease should also not receive the spray, Edwards said.

Some new innovations are happening soon with influenza vaccines, Edwards said. She cited a recent study by Vesikari and colleagues published in Pediatrics, in which the oil-in-water emulsion MF59 adjuvant was added to the avian H5N1 influenza vaccine and the immunogenicity was markedly enhanced. In another recent report from Vesikari and colleagues, healthy children aged 6 months to 18 years, who received the MF59-adjuvanted pandemic H1N1 vaccine, had much higher geometric mean titers.

The effect of adjuvants is “pretty amazing,” Edwards said. “Over the years ahead, we are going to see more vaccines being used with adjuvants.”

Another 2010 study in Vaccine found that adding another oil-in-water adjuvant AS03 to a 2009 influenza A (H1N1) vaccine significantly increased geometric mean titers in children aged 6 to 25 months.

Despite the dramatic effect, “many pediatricians aren’t aware of the use of these adjuvants,” Edwards said. “They need to know about their incredible effect on immune response. The adjuvants are, however, associated with some pain and swelling about 30% to 40% of the time.”

Changing vaccination recommendations

As the threat of the circulating influenza strains continues to be better understood, various organizations tasked with protecting the public health have issued — and reissued — recommendations regarding whom should receive influenza vaccine.

Recently, controversy has erupted over three major organizations’ endorsement of a mandatory vaccination policy for all health care workers. The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America announced their endorsements in early September, and the AAP did so in October.

In a paper published in Infection Control and Hospital Epidemiology, SHEA member Thomas R. Talbot, MD, MPH, and colleagues said several studies found that a 100% vaccination rate among health care personnel in acute care settings triggered a 43% decline in risk for influenza among patients. This decrease appeared even higher (60%) among nursing home patients. Other study data highlighted the cost-effectiveness of health care worker vaccination as a prevention strategy.

“This is a patient safety issue,” said William Schaffner, MD, chair of the department of preventive medicine, Vanderbilt University, in an interview. “Would we permit, for example, a surgeon to decide whether or not to scrub, or whether to use gloves or gowns or masks in an operating room? Of course not. We oblige them to do that, and this is no different.”

Currently, influenza vaccination is not mandatory for health care workers in most states. Last year, vaccination rates in this population were averaging in the middle to high 40% range. The H1N1 pandemic caused a spike in vaccine awareness during the 2009-10 influenza season, and this average increased to roughly 62%.

“That’s not a number we should be terribly proud of,” Schaffner said. “There isn’t any doubt that health care workers can transmit influenza to patients in the course of their professional activities. And there’s also no doubt that the influenza vaccine is effective. If we’re going to put patient care first, then we must mandate it. This concept raises some people’s blood pressure — I recognize that. But as health care workers, we all have to demonstrate we’re immune to hepatitis B virus, that we’re immune to measles, that we’re getting our TDaP vaccination and regular TB tests. Why is this any different?”

Another organization tasked with recommending influenza vaccination schedules, the CDC’s Advisory Committee on Immunization Practices, issued increasingly broad recommendations for the vaccination of children. In 2003, the ACIP called for annual vaccinations for all children aged 6 to 23 months. By 2006, it increased the upper age limit to 5 years. A year later, it recommended two doses of influenza vaccine in all previous unimmunized children younger than 9 years. In 2008, the ACIP issued its broadest recommendation yet: annual vaccinations in all children aged 6 months to 18 years.

The increased sensitivity to influenza “is being driven by the increasing burden of disease and an appreciation that there is a lot of disease out there,” Edwards said. “The pandemic certainly raised everybody’s consciousness.”

Schaffner agreed: “It has become increasingly recognized by professional societies that this is a nosocomial hazard for which we have an inexpensive intervention that we were not effectively using.”

In June, the ACIP issued updates to several of its vaccination recommendations, including influenza, stating that children aged 6 months to 9 years who have not been immunized with the 2009 H1N1 monovalent vaccine receive two doses of seasonal influenza vaccine. The monovalent influenza vaccine produced adequate immune responses in children and adults, according to Anthony Fiore, MD, MPH, a medical epidemiologist for the Influenza Division of the CDC, but study results on how long the vaccine provides protection are lacking.

Research on the seasonal influenza vaccine’s immunogenicity reveals that antibody titers remain lower in young children after inactivated vaccine when compared with older peers and adults.

Still, “vaccination rates for kids under the age of 4 was under 50% [in 2009],” Stan L. Block, MD, Infectious Diseases in Children Editorial Board member, said in an interview. “We get more push back for this vaccine than any other vaccine we give, including Gardasil (quadrivalent human papillomavirus vaccine, Merck). The importance of flu vaccination and the consequences of skipping it need to be discussed in Ladies’ Home Journal, Cosmopolitan, Parents Magazine, Reader’s Digest — everywhere, really — so families and parents can make truly informed decisions.”

Tamiflu and other remedies

When patients become infected with influenza, conventional wisdom dictates a steady regimen of hot fluids and rest. In particularly severe cases, or in patients with certain comorbid conditions, physicians may prescribe antiviral medications, such as oseltamivir (Tamiflu, Roche) and zanamivir (Relenza, GlaxoSmithKline).

Many parents seek to alleviate their child’s influenza symptoms with over-the-counter cold and cough medications, as they see a crossover in influenza and cold symptoms. But, as Edward A. Bell, PharmD, BCPS, author of the Pharmacology Consult section of Infectious Diseases in Children, said the use of many of these products is discouraged by the FDA in children younger than 4 years.

“There was essentially no evidence that they helped young children,” Bell said in an interview. “There was also some evidence that the products were given inappropriately. A few infants even died from the medications.”

In 2008, members of the Consumer Healthcare Products Association volunteered to modify the product labels of OTC cough and cold medicines to read “do not use” in children younger than 4 years. Manufacturers also introduced new child-resistant packaging and measuring systems with their products.

For achy, febrile patients, Bell recommends acetaminophen or ibuprofen. Decongestants containing pseudoephedrine or phenylephrine can be used to ease stuffiness for older children. Nasal suctioning and saline should be used for infants and younger children, he said.

Cough medications are not likely to work, he said, as evidenced by an AAP statement published in Pediatrics stating that “no well-controlled scientific studies were found that support the efficacy and safety of narcotics … or dextromethorphan as antitussives in children,” and that, “suppression of cough in many pulmonary airway diseases may be hazardous and contraindicated. Cough due to acute viral airway infections is short-lived and may be treated with fluids and humidity,” the researchers concluded.

Hot fluids such as chicken soup may act as anti-inflammatories by increasing the effectiveness of neutrophils, a type of white blood cell that is an essential part of immune function, according to Bell.

“It’s not the chicken soup, per se,” Bell said. “It’s just that any warm liquid that makes the throat feel better is worthwhile and should be used over a cough medication.”

A 2007 study in the Archives of Pediatrics & Adolescent Medicine found that a single dose of buckwheat honey was more effective than dextromethorphan or no treatment in relieving children’s nocturnal cough and sleep difficulty caused by upper respiratory tract infection.

“Honey may be a preferable treatment for the cough and sleep difficulty,” the researchers concluded.

Bell supported the study findings. “My professional philosophy is that I don’t recommend products if there are no good clinical studies to back them up,” he said.

Antiviral medications such as oseltamivir and zanamivir are neuraminidase inhibitors, which suppress the influenza virus replication by cutting off virus cells from their host cell.

Earlier the better

For this reason, “it is best if they are taken early, within the first 48 hours of the onset of symptoms,” Bell said. “If a patient has mild flu and is otherwise healthy, you could argue not prescribing these drugs. They’re not cheap and can lead to resistance. I’d only recommend them for patients who are very ill or have underlying health problems, such as pulmonary or other serious conditions.”

Edwards, however, said she sees a wider role for antiviral medications. She said there are randomized, controlled trials of early oseltamivir in children aged 1 to 3 years with influenza. In the treated groups, symptoms resolved an average of 2.8 days more quickly — a significant difference (P<.001). This equated to 2 fewer days of day care absence and 2 fewer days of absence from work for parents.

“There has been some reluctance among pediatricians when it comes to using antiviral therapies in children,” she said. “Doctors are accustomed to using antibiotics, but they are not as accustomed to using antivirals. This study goes to show that antivirals have a role, and that we should seriously consider them.” – Andy Moskowitz

For more information:

• Belshe RB. N Engl J Med. 2007;356:685-696.
• Carmona A. Vaccine. 2010;28:5837-5844.
• Duval X. PLoS Med. 2010;doi:10.1371/journal.pmed.1000362.
• Heinonen S. Clin Infect Dis. 2010;51:887-894.
• Neuzil K. Pediatr Infect Dis J. 2001;20:733-740.
• Paul IM. Arch Pediatr Adolesc Med. 2007;161:1140-1146.
• Reid KJ Jr. Pediatrics. 1998;102(3 Pt 1):661.
• Talbot TR. Infect Control Hosp Epidemiol. 2010;31:987-995.
• Vesikari T. Pediatrics. 2010;126:e762-e770.

Should influenza vaccination be mandatory for health care workers?

Seasonal influenza is the leading cause of vaccine-preventable death in the United States, associated with approximately 36,000 deaths and nearly 200,000 hospitalizations each year. At particular risk are children, elderly, those who are immunocompromised or critically ill — populations that are disproportionally represented in health care settings. Communicable diseases can spread easily in these settings, and acute outbreaks of influenza have been reported in units such as renal transplant, oncology, neonatal intensive care, and pediatrics associated with low health care professional (HCP) influenza vaccination rates.

Nosocomial influenza infections can spread person to person via virus-laden droplets or by contact with respiratory secretions. Infected persons may be contagious for 24 hours prior to the development of symptoms and for up to a week after the illness resolves. Individuals can also be infected and contagious in the absence of symptoms. Consequently, asking HCPs to remain home when ill may not sufficiently protect patients or coworkers from the risk of transmission. There is also a disturbing trend for health care workers to work while ill; an estimated 76% of HCPs work for a mean of 2.5 days with influenza-like illness (ILI). However, worker absences are equally disrupting to patient safety, with 35% of hospitals reporting staffing shortages during the peak of the 2003-2004 influenza season.

Widespread seasonal influenza vaccination of HCPs is associated with reductions in employee illness and absenteeism, expenditures for employees and employers, and patient morbidity and mortality. Universal influenza vaccination is also associated with reduced prescribing of respiratory antibiotics, which has both public health and clinical implications. For these reasons, mandatory annual influenza vaccination for HCPs has been recommended by professional organizations such as the Society for Healthcare Epidemiology, the Association for Professionals in Infection Control, the Infectious Disease Society of America, the American College of Physicians, American Academy of Pediatrics, National Foundation for Infectious Diseases, and the National Patient Safety Foundation. The CDC recommends influenza vaccination for HCPs as a standard of care; this policy has been in place since 1981. The US National Health Objectives for 2010 include a target vaccination rate for HCPs of 60%, but clinical leaders have proposed rates up to 90% to maximize patient safety.

Programs to increase vaccination rates among HCPs have focused on education and motivation, including free vaccine, using incentives and rewards, and having visible leadership support. Modest increases in vaccination rates have been achieved through the use of declination forms for health care workers who refuse the vaccine. However, the limited effectiveness of these efforts led to the realization that a comprehensive patient safety program incorporating mandatory seasonal influenza vaccination of HCPs is the only proven method to increase vaccination rates above 90%. Mandatory programs have been successfully implemented at an increasing number of health care institutions such as the Department of Defense, Virginia Mason Medical Center, and Johns Hopkins Health System to name a few. Progress has been made during the 2009-2010 season, as nearly 62% of HCPs were vaccinated as of January 2010. This is partly attributable to the expansion of mandatory influenza vaccination programs since vaccine coverage among HCPs was almost twofold higher when required by an employer.

Therefore, I believe that evidence is mounting to support the fact that when success is defined as having 90% or greater vaccination rates, only programs that make HCPs influenza vaccination mandatory have been successful. Mandatory influenza immunization for all HCPs is ethically justified, necessary, and long overdue to ensure patient safety. It is the professional and ethical responsibility of HCPs and the institutions where they work to prevent the spread of infectious pathogens to their patients through evidence-based infection-prevention practices including influenza vaccination. The implementation of this policy should be part of a multifaceted comprehensive influenza infection-control program that includes early identification and separation of infected patients; appropriate personal protective equipment such as masks, hand hygiene and cough etiquette; making sure HCPs stay home when ill; and appropriate use of antivirals.

Ed Septimus, MD, is clinical professor of internal medicine at Texas A&M Health Science Center in Houston, Texas.

No one denies that vaccination of health care workers for influenza is beneficial for workers and their employers, families and patients. I strongly encourage it, and we expend tremendous resources yearly to keep participation above 80% at Mayo Clinic. However, making it mandatory as a patient safety policy gives the impression that vaccination is the only way to prevent transmission. In fact, influenza vaccine is possibly the least effective and most frequently unavailable vaccine ever commercially available. Ironically, the vaccinated worker who gets an attenuated case of influenza but is still shedding virus is a far greater risk to patients than the unvaccinated worker who is clearly ill and stays home from work or wears a protective mask and gloves.

As per the position of the American College of Occupational & Environment Medicine, effective influenza control requires a multi-pronged approach, including vaccination of staff AND patients, use of standard precautions (distancing, gloves, masks, hand washing), cough etiquette, visitor control and reasonable absence policies for sick staff. Thus, not only is influenza controlled but so are the other dozens of diseases for which we have no vaccines.

Mandatory influenza vaccination programs have become vogue across the nation, taking on a crusade-like nature, adding another metric to the safety “dashboard.” And yet, the typical outcome measure is compliance rate (not surprisingly close to 100% since jobs are on the line), not the intended outcome: lives saved or protected. A colleague queried Virginia Mason Hospital, the first to go mandatory in 2005, on its nosocomial influenza numbers: none the year before the program, one case the first year it started. The numbers are underwhelming. Remember, influenza is a community-acquired infection.

Let us stick to reason rather than emotion, apply valid infection control policies, and vaccinate health care workers for their own welfare. When we finally have a readily available vaccine that is effective for most/all influenza strains (promising research in progress), then there will be no argument; everyone will get it, and everyone will benefit.

William G. Buchta, MD, MS, MPH, is the medical director of Occupational Health Service at the Mayo Clinic, Division of Preventive, Occupational and Aerospace Medicine, Rochester, MN.