Controversy continues over oseltamivir, but don’t throw the baby out with the bathwater
Controversy continues over oseltamivir, but don’t throw the baby out with the bathwater
Flu season is in full swing. By now, you’ve probably seen droves of patients with flu-like symptoms. But did those patients really have the flu? Of course, you know what the flu looks like: Patients come in with the abrupt onset of fever, mylagias, headaches, malaise, coughs, sore throats and runny noses. Some may have nausea and vomiting. But plenty of other respiratory viruses can present in the same way. And some patients do not come into your emergency department replete with this spectrum of complaints. And what about kids? Young children often pose the greatest challenges for diagnosing and treating the flu because they do not arrive with the full complement of typical symptoms.
Predictive Values for Children
So how do you know if children have the flu? According to the Centers for Disease Control (CDC), in the pediatric population, if you use acute onset of cough and fever as your clinical definition of flu in a region that has a confirmed circulation of influenza virus, you are likely to be correct in your assumption that the child has the flu. For healthy older adolescents, the positive predictive value of fever and cough in that scenario is 79%-88%; for children 5-12 years old, it is 71%-83%; and for children younger than five years, it’s 64%. This contrasts with adults aged 60 and older where the picture of cough and fever has a much lower predictive value.
Testing for the Flu: Speed v. Accuracy
Will testing help you confirm that it is the flu? And what is the role of testing in the ED?
The rapid antigen tests can be a valuable tool for ED physicians because you’ll get the results in about 15 minutes. But realize that you’re sacrificing accuracy for speed. The sensitivity of rapid tests compared with PCR or viral culture ranges from 10%-70%. False negative results can occur quite commonly. By contrast, the specificity of these tests is quite high, generally 90%-95%. So, in the situation where you need to make a decision about the management of a patient, you should not view a negative test result as necessarily dispositive.
In addition, the rapid tests won’t tell you which strains are circulating. PCR and viral culture are considered the gold standard. You may not get a PCR back for several hours, and the viral culture can take days to yield a result. In general, you should plan on making the most of your decisions based on the overall clinical picture.
So, you may be wondering, why test at all? You should test if you feel that the test result will change your treatment of a particular patient. Testing might be important to confirm that influenza is indeed circulating in the community since the likelihood of any given child with cough and fever having the flu is highest when the flu is known to be in the area, literally. Testing also might be valuable when dealing with an institutional environment where additional infection control measures might be needed, such as a chronic care facility or daycare center. Finally, testing might be useful if the child has family members or contacts that are at high risk for complications from the flu.
What Happened Last Flu Season?
What did we see last year? During the 2013-2014 flu season, the rate of outpatient visits, hospitalizations and deaths in children was lower than the preceding year. This year’s vaccine contains the same strains as last year, as these strains were predicted to be circulating again. One of the strains circulating this year, Influenza A(H3N2) has mutated and no longer matches the strain in the vaccination.
How necessary is it to be re-immunized against the flu if the shot is the same as last year? The answer is that antibody titers wane to half their original levels after 6-12 months. Therefore, for a patient to be fully protected, he or she needs to be immunized again this year. Early data from Fall 2014 suggest that the intra-nasal live attenuated flu vaccine may not be as effective in preventing flu in children as it was in 2013.
Since 2004, influenza-associated deaths in children have been collected in the National Notifiable Diseases Surveillance System. This has allowed us to identify high-risk groups. However, this data also reveal that significant proportions of influenza-related deaths occur in children not considered high risk. This has lead to changes in the vaccination recommendations to include all people six months and older (see list below).
According to the CDC, based on data from 30 states, 105 children died from influenza last year. Almost half of those children (47%) were healthy kids with no underlying high-risk medical condition. 43% of all children who required hospitalization also were healthy, normal kids with no risk factors. Contrast this with the percentage of hospitalized adults (10%) who had no risk factors. Of the children with risk factors for more severe disease, those with asthma and reactive airways disease were the most likely to require hospitalization, accounting for about 26% of all pediatric admissions for influenza. In addition, comparing the risk of hospitalization for influenza, healthy children less than 24 months of age fared worse than older adults. As of December 2014, there have been two children who have died from influenza in my home state of North Carolina. One child had an underlying medical condition, and the other was a healthy elementary student with no risk factors.
The majority of children who died from the flu in 2013 were not vaccinated against the flu. So, I recommend that you promote the flu shot for all children. Children who die from influenza usually do so quickly, within a few days of the onset of symptoms. About one-third of the deaths in 2013 occurred either before reaching the hospital or in the emergency department. Perhaps surprisingly, researchers found that previously healthy kids were more likely to die quickly from the flu than children with underlying medical conditions, although the reasons for this observation are not known.
The good news is that the neuraminidase inhibitors oseltamivir (Tamiflu) and zanamivir (Relenza) are likely to be active against the majority of this year’s circulating strains. Oseltamivir is the drug of choice for treating children with influenza. Zanamivir is typically inhaled using a “Diskhaler” device, which is difficult for children to coordinate. Because of this, it is not recommended for treatment in children less than seven years of age (for prophylaxis, it is five years of age) and is contraindicated in children with respiratory disease, including asthma. An intravenous form of zanamivir exists. While it is not yet approved by the FDA, it can be considered in patients who are critically ill.
The Controversy Over Oseltamivir
Oseltamivir is considered controversial by many providers. It costs more than $100 and shortens the course of disease by 29– 36 hours in children if started immediately — within 48 hours of the onset of symptoms.
A 2014 Cochrane review tried to analyze the potential benefits and harms of neuraminidase inhibitors. It attempted to reduce the discrepancies found in prior reviews by including unpublished data to avoid publication bias. However, as the authors of the report state “inadequate reporting put most of the zanamivir studies and about half of the oseltamivir studies at a high risk of selection bias.” In addition, their criteria for study selection included both confirmed and suspected cases of influenza, increasing the likelihood that subjects who did not actually have the disease were included, which could dilute the observed impact of the neuraminidase inhibitors. Finally, their analysis was done in the intention-to-treat population. If those subjects did not actually take the drugs, the bias would be to make the drugs appear less effective.
If the meta-analysis approach is compromised due to flaws in study designs, what do we have left to help us make decisions? Clearly, more research remains to be done, but we do know that multiple studies from the CDC, World Health Organization and independent investigators have shown that timely oseltamivir therapy appears to reduce the risk of complications, hospitalization and death from influenza in children. Based on this, the American Academy of Pediatrics released recommendations for this flu season (see list below).
In addition, the AAP recommended that treatment be considered for otherwise healthy children for whom a decrease in the duration of illness is warranted. The sooner the treatment is started the better. While it is best to start within 48 hours of the onset of symptoms, patients may still derive some benefit if treatment is started later. Remember to consider prophylaxis in high-risk contacts of influenza patients. Chemoprophylaxis is not recommended for infants less than three months. It is not a substitute for vaccination.
What is the downside to giving oseltamivir? The incidence of nausea and vomiting in children is less than in adults but can still occur in about 14% of children. In Japan, there were reports of self-injury and delirium associated with oseltamivir. No major adverse effects have been reported in infants so far. The major downsides to oseltamivir are cost and the risk of increased viral resistance.
Let’s consider the following scenarios and potential treatment options:
Case 1: The Day Care Child
A healthy, 17-month-old boy develops a flu-like illness in daycare. He looks good after he was dosed with an antipyretic at triage. You decide to administer a rapid flu test so that the daycare will know what is going around. It comes back negative. You decide to treat him with tamiflu anyway because the rapid test is not terribly sensitive and this could be a false negative. He meets criteria to treat because he is in a high-risk category due to his age.
Case 2: The Elementary School Student
This is a healthy, six-year-old girl who just developed symptoms consistent with flu this morning. Her teacher had sent home a letter last week informing parents that several children in the class have the flu. She looks good and has no risk factors for a severe course. You discuss tamiflu with the mother. Yes, the risk of severe disease is never zero, but it is acceptably low in this child. Mom is fine with not treating. You ask about household contacts, and no one who lives with this child is in a high-risk group requiring chemoprophylaxis. This child will go home with rest, fluids and antipyretics. Mom is counseled to avoid giving aspirin because of the association of aspirin therapy and Reyes syndrome in patients with influenza.
Case 3: The High School Student
This is a healthy 17-year-old high school junior with classic symptoms of influenza that started last night. Hehas a positive rapid flu test in the ED. He has no medical risk factors for severe disease but is taking four AP courses and studying for midterms. This is a judgment call, in my opinion. This patient likely will be fine; however, he might find a decrease in the duration of his symptoms significantly beneficial. You discuss tamiflu with the patient and his mother. The patient likes the idea of possibly feeling better faster but hates taking medicine. They decline the prescription.
Case 4: The Child with Renal Disease
This is a five-year-old with renal disease, influenza and pneumonia who is going to be admitted to the hospital for IV antibiotics and supportive care. He has had influenza for a week now. Although the earlier treatment is started the better, there may still be benefit from treating with tamiflu later in the course of the disease. Per the American Academy of Pediatrics recommendations, hospitalized children with presumed influenza should be treated with tamiflu regardless of the length of illness. There is no proven benefit from doubling the dose, so standard dosing should be used.
- So what can we conclude in terms of treating children with suspected influenza? While the vast majority of children will be fine, some may not be.
- You should not rely solely on test results when deciding whom to treat.
- Start treatment as early as possible but do not withhold it in patients who have had symptoms longer than 48 hours if they meet the criteria for treatment.
- Don’t forget to ask about household contacts that may be at high risk for severe disease.
- Vaccination is the best defense, not neuraminidase inhibitors. Get plenty of rest, drink fluids and, for starters, get your flu shot!
- Age less than 2 years
- Chronic lung disease, including asthma
- Cardiovascular disease (except hypertension)
- Renal disease
- Liver disease
- Hematological disease
- Metabolic disorders, including diabetes
- Neurologic and neurodevelopmental disorders
- Long term aspirin therapy
- Pregnant or post-partum within 2 weeks (includes teen pregnancies)
- Resident of a chronic care facility
- American Indian/Alaskan native
- Morbid obesity (BMI 40 or above)
Recommendations by the American Academy of Pediatrics
- Treatment should be offered to any child hospitalized with influenza. This should be regardless of their immunization status and should be offered even if they have had symptoms longer than 48 hours.
- Treatment should be offered to children with severe, complicated or progressive illness attributable to influenza. Again, this should be regardless of immunization status or length of illness.
- Treatment should be offered to children with influenza of any severity if they are in a high risk group.
Predictive Values: The odds that acute cough and fever are due to flue
- Adolescents >12 years = 79-88%
- Children 5-12 years = 71-83%
- Children <5 years = 64%
- This contrasts with adults aged 60 and older where the picture of cough and fever has a much lower predictive value
Amy Levine, MD is a professor of pediatrics in the Division of Pediatric Emergency Medicine at the University of North Carolina.
2. Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database of Systemic Reviews 2014, Issue 4.
6. Committee on Infectious Diseases. Recommendations for Prevention and Control of Influenza in Children, 2014-2015. Pediatrics; 2014(5);134.
8.Wong KK, Jain S, Blanton L, et al. Influenza-Associated Pediatric Deaths in the United States, 2004-2012. Pediatrics 2013;132:796.
10. Mistry RD, Fischer JB, Prasad, PA, et al. Severe Complications in Influenza-like Illnesses. Pediatrics 2014;134:e684-690.