Jane M. Carnazzo, MD

Most of North America is now well into what we consider our cold and flu season, when influenza and respiratory syncytial virus (RSV) peak. Every season brings something new, and the 2020-2021 season has been no different. We have all heard a great deal about coronavirus disease 2019 (COVID-19) throughout 2020, and it is the one big variable to this flu season. In practicing general pediatrics for over 30 years, I have seen influenza hit as early as November and still hang around as late as April. RSV seems to come a little later, around January to February, and when the two overlap, pediatricians’ offices are swamped, and hospital beds are full. This year, what does having COVID-19 in circulation mean to pediatricians at the time of year that’s considered the sick season?

Influenza typically presents with a sudden onset of fever and chills with cough and headache. Myalgias, malaise, sore throat, and rhinitis are also common, as well as abdominal pain with vomiting and diarrhea. The presentation will vary, with some patients appearing with severe upper respiratory symptoms and others with few respiratory symptoms yet high fever and fatigue. Influenza is an important cause of otitis media and can cause acute myositis with calf tenderness. In infants, influenza can present as a sepsis-like illness or croup, bronchiolitis, and pneumonia. Most children will recover in 3 to 7 days, but even previously healthy children can develop severe symptoms and complications such as febrile seizures or encephalopathy. Death from influenza-associated myocarditis has been reported.

Respiratory syncytial virus causes acute respiratory infections in individuals of all ages but is one of the most common early childhood diseases. Most infants infected with RSV will have upper respiratory symptoms, and 20% to 30% will develop lower respiratory symptoms such as bronchiolitis and pneumonia with the first infection. Infection with RSV will begin with rhinitis and cough and can progress to increased respiratory effort with tachypnea, wheezing, crackles, and retractions. Fever may be high or low grade, and apnea may occur in those infected during the first few weeks of life. From 1% to 3% of all children infected with RSV in the first 12 months of life will be hospitalized with lower respiratory infections, but most are less than 6 months of age. At increased risk of severe disease are infants with prematurity, chronic lung disease of prematurity, and certain types of congenital heart disease. Yet mortality is rare when supportive care is available. Almost all children are infected by RSV at least once by the age of 24 months, and reinfection is common.

Influenza is spread person to person, primarily through large-particle respiratory droplet transmission requiring close contact between individuals, but is thought to also spread via transmission from contaminated surfaces by hand transfer of influenza virus to mucosal surfaces. It may have the airborne transmission of small-particle aerosols in the vicinity of an infectious person. Similarly, RSV is also spread via direct or close contact with contaminated secretions either by large-particle respiratory droplets or persisting on surfaces for several hours, allowing hand to mucosal surface spread.

 Now that COVID-19 in the mix, health care providers (HCP) see how difficult it will be to determine which patients are infected because there are so many similarities. Health care providers need to remember that coinfection can exist, further complicating diagnoses.

Distinguishing between influenza and RSV can also be difficult, with many symptoms overlapping, but often, with a good history and a full physical, a proper diagnosis is possible. Some distinctions include loss of taste and smell, which may lead pediatricians to think it might be COVID-19 in older patients. As children are harder hit with influenza, the droopy red eyes and high fever with cough should lead pediatricians toward an influenza diagnosis in younger patients. Although RSV can present with high fever, it will cause more wheezing in infants and toddlers.

The incubation period for influenza is 1 to 4 days compared with 2 to 8 days with RSV; 4-6 days being the most common. Now we add COVID-19 to that picture, with a 2- to 14-day incubation period, and it becomes a numbers game and a discussion about who to test. Influenza testing should be done when it will influence clinical management. The decision to test is related to the level of suspicion, local influenza activity, and the sensitivity and specificity of available tests. Nasopharyngeal swabs have the highest yield, but midturbinate nasal swabs are acceptable, and ideally, specimens should be obtained in the first 4 days of illness because the quantity of virus shed decreases rapidly beyond that point as the illness progresses. Rapid RSV testing is also available with nasopharyngeal specimens, and the sensitivity in small children is 80% to 90% with most, but less reliable in older children. False-positive results are likely to occur during periods of low viral circulation for both RSV and influenza testing.

Multiplex assays are available using reverse transcriptase-polymerase chain reaction (RT-PCR) and may be preferred because of increased sensitivity. These tests should be interpreted with caution as more than one virus can be detected: Some viruses can persist in the airway for weeks after the acute infection has resolved (eg, RSV, rhinovirus, and adenovirus).

 We may even add COVID-19 to this list, as some patients have tested positive for weeks after their symptoms have resolved.

No available treatment shortens the course of RSV bronchiolitis or hastens the resolution of symptoms, but supportive care with hydration and careful monitoring of respiratory status is the primary management to alleviate symptoms in the patient. Hospitalization for supplemental oxygen and, if necessary, mechanical ventilation may be required. Neither ßadrenergic agents nor the use of racemic epinephrine is recommended for use in first-time wheezing associated with RSV. Bronchodilators do not improve oxygen saturation or time to resolution of illness. For those at high risk, palivizumab is a monoclonal antibody administered by intramuscular injection and recommended by the American Academy of Pediatrics for monthly administration during the RSV season.

 There are no changes to these recommendations this year.

Influenza may be treated with antiviral medications, including neuraminidase inhibitors (eg, oral oseltamivir, inhaled zanamivir, or intravenous peramivir), endonuclease inhibitors (eg, oral baloxavir marboxil), and adamantanes (eg, amantadine and rimantadine). Oseltamivir is the drug of choice and has been approved for use down to 2 weeks of age. Widespread resistance to adamantanes with H3N2 and H1N1 strains since 2005 has led to neuraminidase inhibitors as the only recommended antiviral drug for influenza. Treatment should be initiated early in the illness as the greatest effect on outcome is achieved if given within 48 hours of the onset of symptoms.1 In one randomized controlled trial, baloxavir marboxil had greater efficacy than oseltamivir in adolescents and adults with influenza B virus infection.

Pediatricians know the when, the how, and the treatment for influenza and RSV, but when COVID-19 is added to the winter mix, the puzzle becomes complicated. Health care providers are already seeing a less severe influenza and RSV season due to the COVID-19 precautions, with individuals wearing masks and continued physical distancing. Some have witnessed a significant drop in the number of febrile illnesses with secondary otitis or sinusitis presenting in office. When daycare centers and schools refuse sick children and clean more efficiently, the spread of any infectious disease will slow. Pediatricians may not remember a fall season with so few group A streptococcal infections. The caveat to this is what it will mean if and when children get coinfections of COVID-19 and influenza or RSV. This is the question of the day as influenza and RSV appear in the community.

What HCPs can do in the meantime is test as many patients as they can to determine the infecting organism and the most appropriate treatment. Antivirals won’t help with RSV and have limited use with COVID-19 infections. Because HCPs know that the 2018-2019 influenza vaccine reduced pediatric influenza A-associated hospitalizations and emergency department visits by 40% to 60%,

 this season’s approach has been to immunize as many children with the influenza vaccine and test as many as possible for influenza and COVID-19. There are many single testing options available and a few multiplex assays using RT-PCR, mostly in hospital labs. However, as the flu season marches on, I anticipate more assays to be available for use in the office as well.

2. Respiratory syncytial virus. In: Kimberlin DW, ed. 

, American Academy of Pediatrics; 2018:682-692.

3. Influenza antiviral medications: summary for clinician. Centers for Disease Control and Prevention. Updated November 30, 2020. Accessed December 7, 2020. 

https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

4. Respiratory syncytial virus infection (RSV): for healthcare professionals. Centers for Disease Control and Prevention. June 26, 2018. Accessed December 7, 2020. 

https://www.cdc.gov/rsv/clinical/index.html

5. Vaccine effectiveness against pediatric influenza hospitalizations and emergency visits. American Academy of Pediatrics. Accessed December 7, 2020. 

https://pediatrics.aappublications.org/content/146/5/e20201368

6. American Academy of Pediatrics. Recommendations for prevention and control of influenza in children, 2020-2021. Accessed December 7, 2020. 

https://pediatrics.aappublications.org/content/146/4/e2020024588

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According to Mark H Sawyer, MD, and professor of clinical pediatrics at the University of California San Diego School of Medicine and Rady Children’s Hospital in San Diego, we should see updates to the guidelines for community-acquired pneumonia (CAP) in 2021. In his session from the virtual 2020 American Academy of Pediatrics National Conference & Exhibition, Sawyer reviewed the present guidelines and discussed the newest approaches to CAP.

A summary of the guidelines recommends hospitalization of infants (3-6 months) for hypoxia and known 

. Use of pulse oximetry is useful to guide severity and is available in the clinic setting, notes Sawyer. Blood cultures, a complete blood count (CBC), and chest x-ray (CXR) have not proven to be helpful in the outpatient setting but does assist in the diagnosis for inpatients. Presently, no urine antigen testing is available as it is with adults. Viral testing is helpful if positive to avoid unnecessary antibiotics, and Sawyer says it is recommended to test for mycoplasma in the school age patient (but not for chlamydophila). Erythrocyte sedimentation rate/C-reactive protein (CRP)/procalcitonin tests may be helpful to follow moderate to severe pneumonia but not in the diagnosis of CAP.

Diagnosis is key to treatment but often signs and symptoms are nonspecific and vary with age. The challenge of diagnosis is furthered by the inability to obtain lower respiratory tract samples. Viruses are the most common cause of pneumonia, but viral and bacterial infections do coexist, and antibiotic management is made more challenging by variable rates of antibiotic resistance in communities, Sawyer reminds us. Community-acquired pneumonia is further complicated now with COVID-19 as well as the increased incidence of vaping. Sawyer did note that ultrasound and nucleic acid-based tests provide some newer advancements in the diagnosis of pneumonia.

 looking at CAP in children, diagnostic methods, and coinfections. The study found the median age to be 2 years of age and that underlying disease increased severity of the pneumonia. Common pathogens included respiratory syncytial virus (RSV), influenza, human rhinovirus (HRV), human metapneumovirus (hMPV) with RSV and HRV the most frequently seen and (no surprise here) seen more in winter months. A sub-study

 of this study, done in 2018 showed 26% of hospitalized children had coinfection, with younger children more likely to have viral infections and coinfected patients sicker.

Sawyer further discussed the tools available for diagnosis with ultrasound a growing alternative to CXR, noting that CXR use is decreasing in emergency departments and use of CRP and procalcitonin is not all that helpful, with blood cultures rarely positive. So, what is promising? Included are the increased use of multiplex polymerase chain reaction (PCR) panels and even 16S rRNA PCR, but in particular metagenomics next generation sequencing. Sequencing detects pathogen nucleic acid in plasma or other sources. Sawyer states that “an unlimited number of pathogens could be identified” and performed quickly.

Treatment in the outpatient setting is often none for preschool-age children, as viral etiologies are more common in this age group. For suspected bacterial disease, amoxicillin is the drug of choice but in the school-age child, the addition of a macrolide may be considered for the coverage of mycoplasma.

Sawyer suggests to test and treat for influenza; for the inpatient, ampicillin is appropriate, unless there is a high level of penicillin resistance in the community. Says Sawyer, “It is important to know your immunization status as ceftriaxone is recommended for those who are unimmunized. If 

 is a concern, then addition of clindamycin or vancomycin should be considered. Pneumococcal conjugate vaccine (PCV) and influenza vaccines are key to the prevention of CAP, yet according to Sawyer “a significant number of children still do not get an annual influenza vaccine” and only 83.9% completed the PCV series in 2015. Sawyer suggests evaluating your personal patient’s vaccination coverage rate for PCV13 and influenza vaccines, and “see if you can raise them.”

Community-acquired pneumonia is a common problem for every pediatrician. Sawyer gave me a different way of looking at pneumonia. I typically think of CAP as bacterial and approach the diagnosis and treatment with this as my focus. We typically use other terms such as bronchiolitis and bronchitis to describe lower respiratory infections in younger children. Even though an appropriate diagnosis, these terms don’t lend you to see the infections as possible pneumonia. Pneumonia can be viral, bacterial, or a combination, as noted with the rate of coinfection.

The important take-home here is to know when to treat with antibiotics and the appropriate choice of antibiotic. In this time of antibacterial resistance, it is key to know what we are treating and not simply empirically treat all with an antibiotic, particularly when a majority are viral.

The ability to identify the cause of pneumonia with better testing such as next-generation sequencing will only enhance diagnosis and treatment. Vaccinating and encouraging parents to vaccinate not only their children but themselves is interwoven in the health care maintenance visit. This is certainly something I deal with every day as a general pediatrician. New vaccines such as PCV (PCV15 and PCV20) can only further decrease the incidence of bacterial pneumonia and you would expect to see a continued decrease in the rates of pen-resistant pneumococcal disease that has been noted since PCV were introduced. With the right tools available, we will be able to diagnose, treat, and prevent CAP.

1. Jain S, Williams DJ, Arnold SR, et al. Community-acquired pneumonia requiring hospitalization among U.S. children. 

. 2015;371: 835-845. doi: 10.1056/NEJMoa1500245

2. Nolan VG, Arnold SR, Bramley AM, et al. Etiology and impact of coinfections in children hospitalized with community-acquired pneumonia. 

. 2018;2018 (2): 179-188. doi: 10.1093/infdis/jix641

Recommendations on the diagnosis and management of community-acquired pneumonia.

Jane M. Carnazzo, MD

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The perfect storm: Influenza and RSV during the season of COVID-19

New guidelines for community-acquired pneumonia

Jane M. Carnazzo, MD

Articles

The perfect storm: In­fluenza and RSV during the season of COVID-19

New guidelines for community-acquired pneumonia

The perfect storm: Influenza and RSV during the season of COVID-19