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Influenza: Recognition, Treatment and Red Flags
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Influenza: Recognition, Treatment and Red Flags
Introduction
Every year, ER waiting rooms, outpatient clinics, and inpatient hospital beds fill up with patients seeking treatment for the miserable symptoms brought on by the influenza virus. This illness does not discriminate and afflicts all ages, from young babies, to the elderly, and everyone in between. Symptoms can range in severity from several days of fever, chills, and cough in bed at home, to weeks of hospitalization, respiratory distress requiring mechanical ventilation, and even complications resulting in death.
Starting in October and often lasting well into spring, flu season tasks healthcare workers everywhere with promoting prevention, quickly and efficiently identifying those infected, and appropriately managing symptoms and any secondary complications that may arise.
An illness affecting the population on such a large scale requires healthcare professionals to stay up to date on disease trends, diagnosis and treatment protocols, and “red flags” of more serious cases in order to minimize the impact of flu season and keep complications and mortality as low as possible.
This course will review disease trends in recent years, common and more insidious symptoms to help identify flu infections, available testing methods and their accuracy, pharmacologic treatments and the importance of their timing, supportive treatments and symptom management, and the “red flags” of dangerous secondary infections and complications.
Upon completion of the course, the reader should be comfortable participating in prevention, identification, and management of the seasonal influenza virus.
Current Practice, Barriers and Need for Continued Education
Influenza is a serious global issue that has been affecting mankind since the beginning of recorded history. Despite medical advances in recent years, flu remains a major public health concern, with up to 20% of the US population being affected annually (13).
Over 200,000 people are hospitalized nationally each year, with around 36,000 deaths. This issue increases on a global level, with 3 to 5 million infections and over half a million deaths each year (14). Those most at risk are young children, those over age 65, and those with other chronic or underlying conditions such as asthma, diabetes, immunosuppression, etc.
Despite high rates of infection and risk of complications, the estimated annual vaccination rate amongst the general population remains fairly low, around 37.1% for adults (3) and 57.9% for children for the 2017-2018 flu season (4). There is an increased rate of vaccination amongst healthcare workers (78.6%), but as these are the people most likely to come in contact with and spread the virus, even that number could be improved upon (6).
Further complicating the situation, influenza virus has several strains and possesses the ability to change its DNA (referred to as “drift and shift”) as it replicates, making it difficult to produce a highly accurate vaccine (2). Because of this, vaccines cannot be created very far in advance if the most current strain is to be targeted. Vaccine shortages can result if new vaccines are not created at a fast enough rate throughout flu season (6).
There are antiviral medications available for prevention and treatment of flu, however this requires proper identification of those infected or most at risk for infection, and the
administration of these medications is typically time-sensitive (5). Health care professionals should be familiar with common symptoms of flu and be comfortable assessing patients, testing for and diagnosing flu.
All of these considerations for flu illustrate the intense need for educated, proactive health care workers to promote vaccines, quickly identify those most at risk or with active infections, and treat effectively in order to keep the impact of flu minimalized.
The National Institute of Health has ongoing projects to keep available resources robust (14), but this research is only as strong as the health care professionals who implement it and are on the front lines of patient care. Staying up to date on current practice is paramount for national and global management of this resilient pathogen.
Learner Exercise
Do you think that the current rate of vaccinations among healthcare providers (78.6%) could be improved?
With up to 20% of the US population being affected annually, do you think enough resources are utilized in the prevention, recognition, and treatment of influenza?
What could be done from a national, state, and local level to promote increased prevention, recognition, and treatment of influenza?
What is Influenza?
Viruses are small pathogens containing genetic material that infect host cells and replicate within that host. They can exist for short periods of time outside of a host as an infectious virion and are spread between hosts through a variety of ways. Influenza is a specific group of RNA viruses that replicate within the epithelial cells of the respiratory tract (15).
There are three main types of flu viruses (A, B, and C). Viruses B and C typically only exist in humans, but A has been found in other mammals such as pigs and horses (15). There are also subtypes of each virus, depending on specific structure of the virus; these are labeled as H1-16 and N1-9 for hemagglutinin and neuraminidase, however, further discussion of these is beyond the scope of this course (15).
As the virus replicates within host cells, there can be subtle changes to the RNA over time, eventually adding up to more noticeable changes and resulting in these different subtypes. These slow changes are referred to as antigenic “drift” and are part of why creating a highly accurate flu vaccine is so difficult (2).
Typically viruses that have drifted some are still susceptible to the current vaccine or there is some acquired immunity within the population. However, there is sometimes a more dramatic structural change referred to as antigenic “shift” that results in a completely new viral subtype and a population with virtually no immunity to this new agent (15). This can result in serious infection of pandemic proportions, such as the 2009 H1N1 outbreak (15).
Influenza viruses are typically spread through droplet transmission, when an infected person spreads microscopic drops of bodily fluids, typically through sneezing or coughing, which then come in contact with another susceptible person (8). These droplets usually only travel across air distances of 6 feet or less, however they can be transferred further via indirect contact such as handshaking or by vectors (surfaces or objects where virions survive temporarily while waiting on contact with the next host) (8).
Once a host touches a contaminated vector and then touches their own mucous membranes (nose, mouth, eyes, etc), they can become infected. Other bodily fluids such as loose stools, vomit, and sputum can contain viral RNA and contribute to disease spread (8).
Learner Exercise
The typical point of replication for influenza is upper respiratory tract, more specifically the nares.
How does this correlate with influenza symptoms?
As you can see, infleunza is spread via many modes. How will you use this information to better protect yourself and patients from influenza infection?
Prevention: Flu Vaccines
Once pathogenicity is understood, providers are better able to prevent spread of infection. The primary and most effective way to help prevent the spread of flu is through a high rate of vaccination in the general population. Current recommendations are for all individuals 6 months of age and older to receive a vaccine unless otherwise contraindicated (8).
It is especially important that those most at risk (children under age 2, adults older than 65, and those with comorbid conditions) and those working with high risk individuals (healthcare and childcare workers) receive vaccines.
For the optimum protection, the goal for vaccine timing should be by the end of October, keeping in mind that full antibody production takes about two weeks after the vaccine is received. Though early vaccination is ideal, a flu vaccine can be administered at any point during flu season and patients requesting immunization later in the season should still be vaccinated (8).
The first time children between 6 months and 8 years of age receive a flu vaccine, they will need 2 doses, 4 weeks apart (8). After receiving 2 doses, children only need 1 dose for all subsequent flu seasons (8).
There are some individuals who should not receive a flu vaccine, but this group is typically very small. Among those who are absolutely contraindicated are infants under 6 months of age and anyone with a previous life threatening reaction to a flu vaccine(6).
It was previously thought that anyone with an egg allergy should not receive the vaccine, since the viral components are grown in an egg medium, however most recent recommendations suggest that this does not cause a reaction for most people and should be reviewed on an individual basis with one’s own primary care provider (6).
Anyone with a history of Guillain-Barré Syndrome should also consult their provider and may be advised to omit the vaccine. Patients with a current cough or cold accompanied by fever may be advised to postpone the vaccine until their symptoms have resolved (6).
Each year, the CDC studies two factors of the current flu vaccine, efficacy and effectiveness. Randomized controlled trials are used to study efficacy, or the intended result, of the vaccine in optimal conditions with healthy participants (6). Less formal observational studies are used to study effectiveness, or how well the vaccine is working in the “real world.”
As previously discussed, antigenic drift and shift mean that the annual vaccine is imperfect and does not always prevent illness as well as intended. For a general idea of the typical effectiveness, we can look at data from recent years: the vaccine was shown to be 48%, 40%, and 38% effective in 2015-2016, 2016-2017, and 2017-2018 flu seasons respectively (6).
Regardless of the lower levels of effectiveness compared to other vaccines, such as MMR, vaccination against flu can still prevent substantial numbers of illness and death when considering the population of the United States.
There are a few side effects to be aware of and to include in patient education with administration of flu vaccines. The most commonly reported side effect is local soreness around the injection site. This occurs in about 65% of patients vaccinated, does not typically interfere with activity, and resolves within a week (6).
More systemic symptoms such as fever, headache, and malaise are sometimes reported, but interestingly these symptoms are reported at similar rates in patients who received a placebo vaccine (6). Rarely, an allergic reaction can occur, ranging from urticaria to anaphylaxis.
Children under age 2 are at a slightly increased risk of febrile seizures, particularly if a flu vaccine is given in combination with Prevnar and DTaP vaccines, therefore timing of routine vaccines in conjunction with a seasonal flu vaccine should be discussed with parents of young children (6).
Though the actual correlation is unclear, there is also a suggested link between flu vaccines and the extremely rare condition of Guillain-Barre Syndrome (GBS). This often life-threatening paralytic condition occurs in about 1-2 people per 100,000 each year, regardless of flu vaccine status.
Ongoing research indicates it is unlikely flu vaccines directly cause GBS and that other triggers such as recent viral illness are more likely to be the culprit, but the CDC estimates there may be a 2 per 1 million chance of experiencing this complication after receiving a flu vaccine (6).
Learner Exercise
How would you react if a patient refused the influenza vaccine due to potential side effects?
What education would you provide?
Standard Precautions
In addition to vaccines as the front line of disease prevention, there are multiple ways to help slow or prevent the spread of disease once flu season starts.
Hand hygiene and cough etiquette are amongst the most effective measures to prevent spread of illness (1). These steps are easy and can be followed by anyone, regardless of if they are ill or not.
Avoid touching your mouth and nose. When coughing or sneezing, use a tissue to cover your nose and mouth and then dispose of the tissue and wash your hands. Handwashing should be done with soap and water or alcohol based hand sanitizer (9). In addition to standard precautions, anyone with respiratory symptoms and/or fever is encouraged to wear a surgical mask.
Hospitals and clinics can help stop the spread of infection by separating well patients from those with respiratory symptoms (1). People who are ill should not attend work or school and should limit their contact with well people as much as possible while symptoms are present (9).
Infected individuals are considered contagious 1-2 days before showing symptoms and up to a week after illness begins; they should be fever free for 24 hours before returning to work/school (9).
Recognition and Treatment of Flu: Symptoms
Despite prevention efforts, hundreds of thousands of people nationwide will contract the influenza virus each season.
When prevention efforts fail, the next important step is early identification. It is important for all healthcare workers to be familiar with the symptoms of flu and be able to quickly and accurately identify those with a probable diagnosis of flu.
Typical influenza infections start suddenly with a combination of fever, headache, sore throat, fatigue, nasal congestion or runny nose, body aches, and chills.
Fever and acute symptoms can last more than 7 days, with fatigue and weakness lingering for weeks. While fever is typical of influenza infection, not all who are infected present with a fever (15).
Testing for Influenza
It should be noted that patients with suspected flu can be treated purely based on clinical presentation and regional flu trends at that time; rapid flu tests do not have the highest sensitivity and therefore should not be the determining factor in regards to the necessity of treatment. However, there are several methods of testing for flu that can help confirm a suspected diagnosis of flu.
There are two main types of testing for flu, molecular assaysand antigen detection tests. Molecular assays work by identifying viral nucleic acids or RNA in a respiratory specimen (7). They are highly sensitive and specific, meaning they can detect the virus at even very low levels and the risk of false positive is very low.
There are rapid molecular assays that can result in as little as 15 minutes, identifying flu A or B, and there are also Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and nucleic acid amplification tests available which take closer to 45 minutes to an hour for results and can identify specific subtypes of flu for a more in depth diagnosis (7). Antigen detection tests are typically used in outpatient settings due to their cost effectiveness and rapid results (10-15 minutes) These rapid tests are up to anywhere from 50-70% sensitive and have specificity >90% (7).
While more accessible to the clinic setting, antigen detection tests are less accurate and a negative result does not exclude a diagnosis of flu. In cases where flu is highly suspected and a rapid test result is negative, the result can be confirmed with a molecular assay or treatment can be started based on clinical presentation and a presumed false negative test result (7).
In fact, where high risk populations are concerned, such as asthma, heart disease, immune disorders, and other comorbid conditions, prompt treatment when flu is suspected is recommended regardless of testing results (7).
Viral cultures are also available for the most in-depth results. While not practical for the clinical setting due to long result windows (3-10 days), viral cultures offer extremely detailed and useful information about the genetic details of current flu strains which is helpful when developing the next year’s vaccine (7).
Learner Exercise
Influenza testing is nuanced and rapid testing cannot be relied upon for diagnosis.
Does this mirror what you see or do in clinical practice?
How could improved education of healthcare providers lead to more accurate diagnosing and treatment of influenza?
Treatment
Once flu has been identified clinically and laboratory confirmation is obtained (if desired), treatment of flu should be started as quickly as possible in order to maximize benefits of treatment and minimize potential complications of untreated illness.
Three antiviral medications known as neuraminidase inhibitors are available by prescription in the US (oseltamivir, zanimivir, and peramivir). These medications work by blocking neuraminidase, an enzyme that allows newly replicated influenza viruses to be released from host cells (5). Another antiviral, baloxavir, works by stopping replication of the virus within the host cells (5).
Treatment should ideally be started within 48 hours of symptom onset, however there may still be benefits for severely ill patients or those who are very young, elderly, suffering from comorbid conditions, or already hospitalized, and treatment initiation after 48 hours may be considered (5). Treatment should also never be delayed while awaiting laboratory results (5).
Treatment may be initiated based on clinical symptoms alone, if symptoms are highly suggestive of influenza during an endemic period. The decision to treat is based on many factors, including risk of complications and time since symptom onset.
The most common side effects of these medications include nausea, vomiting, headache, dizziness, and sometimes a skin reaction. Typically, these medications are well tolerated and prompt initiation of treatment should be encouraged (5).
In addition to antivirals, supportive care is a mainstay of treatment. Rest, hydration, cool mist humidifiers, antipyretics, and throat lozenges have all been shown to provide comfort and help with symptoms. Multiple studies have shown honey to be an effective cough suppressant and 1 tbsp in warm tea or water can work well to provide some relief.
Patients should be monitored for signs of dehydration, including dry mucous membranes and reduced urine output. Ill patients should also isolate themselves as best as possible to prevent further spreading the illness (12).
Learner Exercise
Which patients are at highest risk of influenzas complications, including death?
Is it justified to treat these individuals based on positive clinical symptoms even with a negative rapid test? Is it justified to treat them after 48 hours?
“Red Flags” – Potential Complications and What Not to Miss
The majority of flu cases make a full recovery after 1-2 weeks of illness, however there are some more serious complications that can develop, including life-threatening symptoms and even death (11). Flu can sometimes trigger systemic inflammation, leading to myocarditis, encephalitis, rhabdomyolysis, or multi-organ failure.
These conditions can be difficult to diagnose if suspicion is not high. Flu infections attack the usual defenses of the respiratory tract and predispose the body to secondary bacterial infections like pneumonia.
The body’s initial inflammatory response is beneficial to help the body fight off a flu infection, but increasing inflammation or prolonged inflammation puts too much stress on the body and this extreme response can result in autoimmune disorders or sepsis (13). Those with asthma, heart disease, or other chronic conditions are at an increased risk of complications, as are young children and the elderly (11).
Post-influenza pneumonia is a well-described phenomenon and the most common causative pathogen is Methicillin-resistant Staphylococcus Aureus (MRSA). This secondary infection should be considered in patients with respiratory symptoms and/or sepsis after a recent resolution of flu followed by returning or new/acute symptoms. It is important to consider MRSA as a causative agent when prescribing antibiotics to patients with post-influenza pneumonia (15).
“Red Flags” or warning signs that the body is working too hard to deal with the flu virus or is not compensating well include: fast respiratory rate or difficulty breathing, cyanosis, tachycardia, hypotension, chest pain, dizziness, confusion, decreased urine output (>8 hours), severe muscle pain, or seizures. In children, fever >104 (or any fever in children <12 weeks of age) and retracting are concerning signs.
Any other signs/symptoms that are concerning or seem to be worsening warrant further workup and possible hospitalization to prevent further decline (11).
Learner Exercise
Have you ever seen a patient who displayed “red flags”?
How would this change the patient’s management and what type of treatment / monitoring would they need?
Case Study 1
This case study involves a real patient’s experience with seasonal flu. Names, genders, ages, and some details have been changed to protect patient information.
Jennifer is a 35 year old female who presents to an urgent care clinic in mid February with 2 days of rhinorrhea, cough, sore throat, body aches, and tactile fever. She has not received a flu vaccine this season. Following triage, her vitals are recorded as: HR: 110, RR: 22, Temporal temp: 101.3, SPO2: 97%, BP: 110/76.
She is visibly uncomfortable but sitting up on the exam table and able to cooperate and carry on a conversation. She is breathing a little shallowly and has a frequent, coarse sounding cough, but is overall not in any respiratory distress. She is congested and has clear rhinorrhea, eyes are watery, she has some posterior pharynx erythema, no cervical lymphadenopathy, and some faint rhonchi to her lungs that she is able to clear when coughing.
Rapid strep and rapid flu swabs are collected and the results are negative. She is given a prescription for 5 days of 75mg BID TamifluⓇ (oseltamivir) which she fills and begins taking that afternoon. A viral culture is collected from her via nasopharyngeal swab for confirmation of suspected influenza.
Within 3-4 more days, Jennifer is fever free and beginning to feel better despite some persistent fatigue. She works from home until her fever has resolved and cough is improving. She makes a full recovery without sequelae. Three days later her viral culture indicates she has type B influenza, despite her negative rapid influenza test. This is a typical case of influenza and the
Tamiflu may have hastened her recovery and possibly prevented severe illness. It also illustrates that rapid influenza testing has a low sensitivity and per CDC guidelines treatment may be based on clinical signs and symptoms.
Case Study 2
This case study involves a real patient’s experience with seasonal flu. Names, genders, ages, and some details have been changed to protect patient information.
Braxton is a 9 year old male who presents to his PCP’s office with sudden onset of high fever (tmax 103), headache, and cough that started that morning. It is December and he has not received a flu vaccine. His vitals are stable.
Exam reveals clear rhinorrhea, erythematous and enlarged tonsils, and frequent barky cough. Rapid strep is negative and rapid flu is positive for Influenza A. He is given a prescription for tamiflu (oseltamivir), however his parents have some reservations about the medication due to an article they read on social media and decide not to give him the medicine.
They manage his symptoms with analgesics, gatorade, and rest. About 11 days later he follows up in the office with complaints of persistent fatigue and new complaints of dizziness and abdominal pain. Parents report a syncopal episode at home that morning, prompting today’s visit.
His cough is still present, but better than it was, and he has been afebrile for about 5 days now. He looks very pale and complains of some dizziness as he gets up onto the exam table, his behavior is sluggish. He has some abdominal bloating and tenderness with mild spleen enlargement. He has lost 4 lbs since his previous visit. Vitals are somewhat concerning: HR: 145, RR: 27, Temporal temp: 98.8, SPO2: 98%, BP: 90/54.
He seems poorly hydrated and his overall appearance is concerning so you order some stat labs. Multiple abnormal lab values return, the most critical of which is a hemoglobin of 3.4. He is admitted to the local children’s hospital PICU and treated for hemolytic anemia secondary to viral infection as well as multisystem organ failure.
After multiple blood transfusions and aggressive steroid therapy, he is discharged home after over two weeks of hospitalization with no permanent organ damage.
This case illustrates one of the rae (but potential) complications of the viral influenza infection. It is possible that early antiviral treatment may have avoided this complication and/or minimized it.
Summary
While influenza is an annual problem and can often seem routine, it is of utmost importance that healthcare professionals stay vigilant in their knowledge of flu and treat each case on an individual basis.
As the front lines for promotion of flu prevention, early identification and treatment of flu, and maintaining alertness for potential complications, health care workers can have the biggest impact on the severity of the current flu season.
Staying up to date on current practice can help reduce overall numbers of infection, rate of complications, and mortality.
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References (Bibliography)
(1) Centers for Disease Control and Prevention. (2012). Respiratory hygiene/cough etiquette in healthcare settings. Retrieved from:
https://www.cdc.gov/flu/professionals/infectioncontrol/resphygiene.htm
(2) Centers for Disease Control and Prevention. (2017). How the flu virus can change: “drift and shift”. Retrieved from: https://www.cdc.gov/flu/about/viruses/change.htm
(3) Centers for Disease Control and Prevention (2018). Estimates of flu vaccination coverage among adults- US 2017-2018 flu season. Retrieved from: https://www.cdc.gov/flu/fluvaxview/coverage-1718estimates.htm#ref3
(4) Centers for Disease Control and Prevention (2018). Estimates of flu vaccination coverage among children- US 2017-2018 flu season. Retrieved from: https://www.cdc.gov/flu/fluvaxview/coverage-1718estimates-children.htm
(5) Centers for Disease Control and Prevention. (2018a). Influenza antiviral medications: summary for clinicians. Retrieved from: https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm#
(6) Centers for Disease Control and Prevention. (2018b). Influenza vaccination: a summary for clinicians. Retrieved from: https://www.cdc.gov/flu/professionals/vaccination/vax-summary.htm
(7) Centers for Disease Control and Prevention. (2018c). Overview of influenza testing methods. Retrieved from: https://www.cdc.gov/flu/professionals/diagnosis/overview-testing-methods.htm
(8) Centers for Disease Control and Prevention. (2018d). Prevention strategies for seasonal influenza in healthcare settings. Retrieved from: https://www.cdc.gov/flu/professionals/infectioncontrol/healthcaresettings.htm
(9) Centers for Disease Control and Prevention. (2018e). Preventing the flu: good health habits can help stop germs. Retrieved from: https://www.cdc.gov/flu/protect/habits/index.htm
(10) Centers for Disease Control and Prevention. (2018f). Prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization