Submitted by Susan B. Yox, RN, EdD, Richard J. Whitley, MD
Alabama was one of the first states to be hit hard with influenza. In light of that, Susan B. Yox, RN, EdD, of Medscape spoke with Richard Whitley, MD, Distinguished Professor of Pediatrics; Loeb Scholar in Pediatrics; Professor of Pediatrics, Microbiology, Medicine and Neurosurgery, at The University of Alabama at Birmingham, and a member of the Infectious Diseases Society of America's Influenza Advisory Group, about the diagnosis and management of influenza. Among other advice for managing an influx of patients with possible flu, Dr. Whitley describes his experiences with clinical decisions such as which patients should be hospitalized and who can be safely managed at home during the ongoing influenza season. He also addresses the important issue of antiviral treatment and why he believes it is an essential component in the fight against influenza.
Dr. Whitley: I need to give you a little bit of background. Until a week ago, I had been on our clinical service since Thanksgiving, so I have watched this unfold in our emergency department and in our inpatient service here at Children's Hospital of Alabama. Alabama was one of the first states to experience a surge in the number of cases of influenza, not only in children but also in adults. But the wave came in children first, which is very interesting. A couple of observations have been made. One is the CDC hypothesis that we saw influenza early this year because children went back to school and mingled with other students, causing an increase in the rate of transmission.Medscape: Reports indicate that 20 children have died from influenza this season, and last week, the Centers for Disease Control and Prevention (CDC) reported that 47 states are experiencing widespread influenza. Patients with symptoms of influenza are overwhelming emergency departments. Would you offer our clinician audience some insight? Do you believe that this will be a record-breaking influenza season or is this perhaps just a quick beginning to an expected seasonal surge in influenza?
That can't be the only explanation because, beginning early in December and even by Thanksgiving, we were hospitalizing children with influenza pneumonia and bacterial infections secondary to influenza infection. We have had many children hospitalized as a result of supplemental oxygen requirement, and some have required ventilatory support. We have had no deaths yet at Children's Hospital of Alabama, but we have seen a significant number of children who developed secondary bacterial complications in the form of Staphylococcus aureus (community-acquired, methicillin-resistant) or streptococcal infections of the lung that have required surgical drainage because of empyema.
The other observation that I have made, because I'm also responsible for our diagnostic virology laboratory, is that at the beginning of the season we saw many cases of influenza B. As we moved into December, the epidemiology of the infection changed so that we saw H3N2, which is now the predominant strain of influenza that is circulating in the communities across the United States. It is as though influenza B is playing a secondary role. H3N2 is the virus that we worry about the most because it's more severe than H1N1 or even 2009 H1N1. That has attracted a lot of attention.
Medscape: So, you believe that this is already a particularly worrisome year for influenza?
Dr. Whitley: Yes. The CDC reports that it is beginning to wane in some states, but it's not waning at Children's of Alabama. We have been at this now for 8 weeks, and we are seeing 260 visits to our emergency department daily, when we normally see about 100-150. It isn't just influenza. We are also seeing other respiratory infections that are common at this time of year in children under 2 years of age, particularly respiratory syncytial virus infections. But the predominant illness is influenza.
Medscape: Can you offer any comment on what is happening in adults?
Dr. Whitley: We are also seeing flu in adults. We find that the adults in Birmingham tend to get immunized, whereas many families forget that their children need immunization as well. That is an important point: We have to make sure that our children are immunized.
Medscape: The next question relates to the virus strain in circulation right now. The most common strain is the H3N2, and 36%-37% of influenza A specimens are of unknown subtype. Is it common for laboratories to not subtype such a high percentage of specimens?
Dr. Whitley: Yes, it is common, and it reflects a couple of different trends that are occurring. Most diagnostic virology laboratories just report influenza A or influenza B, and they don't bother to subtype the specimens. If a virus specimen is sent to the state health department, it will ultimately be typed. But there is a significant lag phase of 4-6 weeks before the typing is complete.
So, the specimens that haven't been typed yet will eventually be typed. But I don't think that we are dealing with a new strain of influenza that we are not aware of yet. If that were the case, we would already know it because the deep sequencing that is being done at the CDC would have identified those cases by now. So I don't think we are dealing with a 2009 H1N1.
Medscape: Diagnostic testing is another question that commonly comes up with clinicians. The rapid test carries the potential for false-negative results, and there is some guidance from CDC that clinicians should move forward with treatment if symptoms indicate influenza. Could you comment on the limitations and best practices with rapid diagnostic testing?
Dr. Whitley: Our emergency department does rapid influenza testing because, at least at this hospital, we are firmly committed to administering antiviral medication to children who are sick. In a pediatric emergency department, the specificity of rapid testing is high. If the test is positive, the patient has influenza. The sensitivity is not as good as the specificity. In other words, you are going to get false negatives with a rapid diagnostic test.
If we translate this now to adults, the probability of getting a false negative is even higher because the virus load in adults is lower. You are less likely to detect an infectious virus in an adult than in a child. The guidelines that we have used during influenza season say that if a child comes in and the rapid test is negative, but the child is not hypoxic and doesn't require hospitalization, we treat that child empirically as long as we can get oseltamivir.
We have criteria for treatment, and every patient who is hospitalized will be subtyped according to the strain. In other words, is it 2009 H1N1, is it seasonal H1N1, is it H3N2, or is it influenza B? If it's influenza B, which strain is it? We then go one step further and look for the 274Y mutation to determine whether the child already has a virus that was circulating in the community that is resistant to the existing neuraminidase inhibitors. We go the extra mile in the way that we provide care, and I think it is beneficial.
Medscape: How do you treat the child who has a resistant virus?
Dr. Whitley: We treat the child symptomatically if the child is not critically ill, or we give combination therapy with oseltamivir and rimantadine. Some experimental protocols use 3 different drugs (rimantadine, oseltamivir, and ribavirin). That is the only experimental protocol that is used in the community right now.
Medscape: Let's talk about treatment in young children. Oseltamivir was recently FDA-approved for use in infants as young as 2 weeks old, but the average primary care clinician in an office or in an emergency care setting might be concerned about giving it to a child that young. Would you review the recommendations in very young children?
Dr. Whitley: Yes, but I have to admit up front that I have a bias because I am one of the 2 people responsible for the data that led to that recommendation. We generated those data through the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group, which were provided to Roche and Genentech and used to extend the licensure for oseltamivir to children less than 2 years of age.
We did a pharmacokinetic/pharmacodynamic study in children less than 2 years of age so that we could determine the dose that should be used in those children. This study grew out of the public health needs identified with the 2009 H1N1 epidemic experience. We were able to unequivocally show that the dose that should be used in children, up to about 9 months of age, is 3 mg/kg/day. Between 9 months and 1 year of age, the dose should increase to 3.5 mg/kg/day. After 1 year of age, you can go back to 3 mg/kg/day. Most physicians will use 3 mg/kg/day dosing. (Editor's note: For CDC's guidance on dosing in children, see CDC's Seasonal Influenza: Antiviral Drugs.)
A couple of important lessons were learned from that study. First, children got better fast. We had entry criteria that demanded that children be admitted to the hospital within 48 hours after the onset of disease, rather than 72 hours as in many other studies. Second, we learned that the drug was incredibly safe, which addresses concerns from Japan that there were neurotoxic effects of the drug. We absolutely did not see that at all. The patients did exceedingly well and there were no adverse events.
Our strategy at Children's Hospital of Alabama is as follows: If a child comes walking into the emergency department and everybody in the family has influenza, and the child is a little achy and has a low-grade fever but isn't really sick, we don't worry about that child because that child probably has partial immunity and doesn't warrant immediate intervention with an antiviral drug such as oseltamivir or zanamivir.
On the other hand, if the child comes in with a 104° F fever, we definitely are going to go ahead and treat that child, which is a little bit different from some of the recommendations that you may have heard from the CDC during the 2009 H1N1 pandemic. At that time, people said, "We don't need to worry about treating influenza." I think we do need to worry about treating influenza because we can reduce the probability of otitis media, secondary bacterial infections, and the probability of hospitalization (although the latter endpoint is observational and doesn't come from controlled clinical studies).
Medscape: That leads to the next question. For clinicians who are seeing people in offices and emergency rooms, decisions in some situations are obvious. In those patients who are more borderline, do you have any advice about the decision to treat at home or in the hospital?
Dr. Whitley: That is pretty straightforward for me. You can manage most adults at home unless they are really in distress or have an infiltrate on a chest x-ray, and you are worried that the patient might require respiratory support. In children, the criteria are simple: If the child is hypoxemic (a transcutaneous oxygen saturation of less than 92%) and tachypneic, that child is usually hospitalized. We are going to make sure that that child is stable in the hospital before we do anything else.
We observe these children in the hospital for a period of time. We generally require that they be off of oxygen overnight, maintaining their oxygen saturation concentrations above 92% before we let them leave the hospital. I have had children in for 5 days because we can't maintain their oxygen concentrations.
Medscape: Are there any shortages of antiviral drugs for children in particular?
Dr. Whitley: Canada is releasing their stockpile of oseltamivir so that they can make oseltamivir available, not only for children but also for adults. We have had shortages of the pediatric formulation of oseltamivir in the United States as well. The oseltamivir shortages were recognized by Roche/Genentech as early as the middle of November. According to their press releases, they are backfilling their suppliers as quickly as possible so that they can get the drug into the field.
I have not had a problem obtaining drug here in Birmingham. However, I have colleagues who are infectious disease physicians in surrounding states (particularly Florida and Georgia) where they have not been able to get oseltamivir. This problem also happened during 2009 H1N1. I would have hoped that we would have had drug available for these children.
Medscape: Do you know whether the clinicians in Florida and Georgia have been able to get the drug they need? Does it just take longer?
Dr. Whitley: They have to compound the adult drug for children.
Medscape: What is your bottom-line advice for people who are out in the trenches? What might they expect in the next couple of weeks and months?
Dr. Whitley: My first bit of advice is that if influenza is in your community, it would be worth trying to immunize your patients now, if they haven't already been immunized. In Madison County, Alabama, public health officials went into the school system yesterday, and every child who had an informed consent but had not yet been immunized received FluMist intranasally. They had a 95%-98% uptake rate, which was fantastic. We have to be creative in how we immunize people; we haven't totally lost the opportunity to immunize children and adults, and we should remember to try and do that. That's the first thing.
The second thing is that if you are sick, don't go to work because you are going to infect somebody else, and then you will have 2 people out of work rather than 1.
The third point is that if people are sick, they should seek medical attention (eg, 103° or 104°F fever, shortness of breath, tachypnea, abdominal pain). These individuals require medical attention and are likely going to require treatment with a drug such as oseltamivir or zanamivir.
What do I expect is going to happen over the next 4-6 weeks? Influenza is going to begin to abate in states such as Alabama because we expect the season to last about 3 months, and we have been at it for 2 months. I have another month to go here dealing with sick children and adults. I am anticipating that it will continue for about another 4 weeks and then gradually back off. We were among the first states to be hit, so I expect that we will be among the first states to get over it, too.
Medscape: So, other clinicians who just got into a surge of influenza in the past 3-4 weeks may have a couple of months to go?
Dr. Whitley: Yes, such as California. California has seen very little influenza. The entire West Coast, for that matter, is just beginning to see influenza. I expect that the flu is going to be more protracted in the state of California than it will be in the Southeast.
Medscape: Do you have any other advice for clinicians?
Dr. Whitley: Whether we are healthcare providers or not, we took the 2009 H1N1 as a simple little breeze and we didn't pay that much attention to influenza. With influenza, we are going to see severe disease. We can never let our guard down. We always need to remind ourselves that when it's time to get immunized, get immunized. We need to pay attention to the public health issues that surround this disease, whether we are physicians, healthcare providers, or laymen. It doesn't make any difference. We need to do better.
Kimberlin DW, Acosta EP, Prichard MN, et al; for the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza. J Infect Dis. 2013 Jan 10. [Epub ahead of print]