Note: This is the fifth of a series of clinical briefs on the coronavirus outbreak. The information on this subject is continually evolving. The content within this activity serves as a historical reference to the information that was available at the time of this publication. We continue to add to the collection of activities on this subject as new information becomes available.

Clinical Context

The world continues to monitor the outbreak of 2019-nCoV with dread. According to the World Health Organization (WHO) Situation Report on 2019-nCoV dated February 10, 2020,^[1] there were 40 554 cases of confirmed 2019-nCoV infection worldwide (with 909 confirmed deaths). Only 319 of these cases have been diagnosed outside China, with 12 cases diagnosed in the United States.

Although highly concerning, these numbers are dwarfed by the number of individuals affected by influenza in the United States alone in the 2019-2020 flu season. The Centers for Disease Control and Prevention (CDC) estimates at least 22 million cases of influenza in the United States this flu season, with 210,000 hospitalizations and 12,000 deaths.^[2] Although this flu season has been remarkable for the predominance of influenza B strain infections, the CDC notes that the rate of infection with influenza A H1N1 has been on the rise over the past several weeks. In addition, whereas the overall rate of hospitalization because of influenza is similar to previous years, this flu season has resulted in higher rates of hospitalization among children and young adults.

According to these numbers, it is currently much more likely to encounter a patient with influenza vs 2019-nCoV in the United States, but how else can clinicians differentiate between 2019-nCoV and influenza?

Synopsis and Perspective

In a sad twist of events, on February 6^th, the New York Times reported that the Chinese doctor, Li Wenliang, who was said to have blown the whistle on the deadly 2019-nCoV, died from the same virus on January 31 2020. According to media reports, on a social media post, Dr Li described his symptoms, which initiated with a cough on January 10 and followed by a fever the following day. There is not much else reported on his symptoms until his pronounced death on January 31.

There is a limited number of studies on the clinical presentation of patients with confirmed 2019-nCoV infection. What has been garnered in information is primarily from case studies from patients admitted to hospitals in Wunan, China. Most of these are of hospitalized patients with pneumonia, according to the CDC.^[3]

One such study is by Nanshan Chen, MD, et al.^[4] Their retrospective, single-center study on patients recruited from Jinyintan Hospital in Wuhan China, who contracted the virus between January 1 and January 20, provides an early look at clinical and epidemiological characteristics of the virus in 99 confirmed cases.

How does the flu differ from 2019-nCoV? One common factor is that both are respiratory illnesses but are caused by different viruses.

Signs and Symptoms

Chen et al identified the following symptoms of 2019-nCoV that were presented in 99 patients on onset^[4]:

• Fever, n= 82 (83%)
• Cough, n= 81 (82%)
• Shortness of breath, n= 31 (31%)
• Muscle ache, n = 11 (11%)

Of the symptoms, the fever course is not fully understood among patients who contracted the 2019-nCoV infection. According to the CDC,^[3] it may be prolonged and intermittent. Serious 2019-nCoV infection can develop into severe pneumonia, pulmonary edema, acute respiratory distress syndrome, or multiple organ failure and death, according to Chen and colleagues.^[4]

In another study by Qun Li, MMed, et al,^[5] which analyzed the first 425 confirmed cases of 2019-nCoV, researchers diagnosed infection as pneumonia if it fulfilled the following criteria:

• Fever (with or without recorded temperature)
• Radiographic evidence of pneumonia
• Low or normal white-cell count
• Low lymphocyte count
• No reduction in symptoms after antimicrobial treatment for 3 days

Pneumonia was confirmed if patients had the first 3 criteria and had an epidemiologic link to the Huanan seafood market or came in contact with patients with similar symptoms.

What are the signs and symptoms of the flu? These are often sudden and include fever, cough, sore throat, runny or stuffy nose, muscle or body aches, headaches, fatigue (tiredness), vomiting, and diarrhea (more common in children), according to the CDC.^[6]

As you can see, the 2019-nCoV symptoms are similar to that of the flu. It is safe to conclude that it is impossible to tell for sure if a patient has the flu according to symptoms alone.

Incubation Period

According to the CDC interim clinical guidance,^[3] the incubation period of 2019-nCoV is said to be approximately 5.2 (95% CI: 4.1, 7) days. Li and colleagues estimated the duration from illness onset to first medical visit for 45 patients with illness onset before January 1 2020 to have a mean of 5.8 (95% CI: 4.3, 7.5) days, which was similar to that for 207 patients with illness onset between January 1 2020 and January 11 2020, with a mean of 4.6 (95% CI: 4.1, 5.1) days.^[5]

Similarly, for the flu, the CDC states that the show of symptoms from time of exposure is about 2 days but can range from about 1 to 4 days.^[6] It is noted that the first 3 to 4 days tend to be the most contagious with persons infected with the flu.^[6] People with weakened immune systems and young children may be able to infect others for an even longer time.^[6]

In this, 2019-nCoV bears similarity to the flu virus as well.

Clinical Course

Among reported cases of 2019-nCoV infection so far, disease severity has varied between asymptomatic infection and mild to severe or fatal illness. Current clinical course is unclear, but according to the CDC, some reports suggest that patients tend to take a turn for the worse during the second week of illness.

According to the study by Li et al, the mean duration from onset to hospital admission was estimated to be 12.5 (95% CI: 10.3, 14.8) days among 44 cases with illness onset before January 1, 2020 which was longer than that among 189 patients with illness onset between January 1, 2020 and 11, 2020 (mean, 9.1 [95% CI: 8.6, 9.7]) days.^[5]

In contrast, for uncomplicated flu infection, signs and symptoms have a shorter course and usually resolves after 3 to 7 days for most people, although cough and malaise may linger, which can persist for >2 weeks for individuals with weakened immune systems, such as the elderly and persons with chronic lung disease, explains the CDC.^[7]

Diagnostic Testing

Several assays are currently under development that detect 2019-nCoV, both in-house and commercially; however, at this time, US diagnostic testing for 2019-nCoV can be conducted only at the CDC.^[8]

For the flu virus, a number of diagnostic tests, such as rapid influenza diagnostic tests (RIDTs), are available.^[9] Nasal cultures are the most important test for detecting the flu (ideally performed within the first 4 days of illness).^[9]

Laboratory and Radiographic Findings

In the study of infected patients by Chen et al,^[4] according to imaging examination (chest x-ray and computed tomography [CT]) results, 75% of patients showed bilateral pneumonia, 14% of patients showed multiple mottling and ground-glass opacity, and 1% of patients had pneumothorax; 17% of patients developed acute respiratory distress syndrome, and among them, 11% of patients worsened in a short period of time and died of multiple organ failure.

Laboratory results from patients with 2019-nCoV pneumonia showed increased leucocytes in 24% of patients, increased neutrophils in 38%, and decreased lymphocytes in 35%; platelets increased in 4% of patients.^[4] Blood biochemistry showed decreased albumin in 98% of infected patients and elevated liver function tests: alanine aminotransferase (28%) and aspartate aminotransferase (35%).^[4]

The flu can be complicated by secondary bacterial infections such as pneumonia. Similar to 2019-nCoV, other tests to detect radiographic findings can be performed (ie, chest x-ray or CT scan, sinus x-ray or CT scan). Laboratory findings may show an elevated white count when secondary bacterial infection is present or low white count if a viral infection is present.

Clinical Management and Treatment

The CDC recommends minimizing exposure to 2019-nCoV.^[3] Isolation is recommended for all patients infected with 2019-nCoV as well as implementation of infection control measures.^[3]

Currently, no specific treatment for 2019-nCoV is available.^[3]

According to the study by Chen et al,^[4] 76% of patients infected with the 2019-nCoV received antiviral treatment. This included oseltamivir dosed at 75 mg every 12 hours orally, ganciclovir dosed at 0.25 g every 12 hours intravenously, and lopinavir and ritonavir tablets dosed at 500 mg twice daily orally. Treatment duration ranged from 3 to 14 (median, 3 [interquartile range [IQR], 3-6]) days. Antibiotic treatment was administered to 71% of patients as well (ie, cephalosporins, quinolones, carbapenems, tigecycline against methicillin-resistant Staphylococcus aureus, linezolid, and antifungal drugs). About 45% were given combination antibiotic treatment. Duration of antibiotic treatment ranged from 3 to 17 (median, 5 [IQR, 3-7]) days. Supportive treatments of steroids (eg, methylprednisolone, dexamethasone) were administered as well, with a duration of 3 to 15 (median, 5 [IQR, 3-7] days).^[4]

For people with influenza infection or who have a high risk for serious complications, the CDC recommends prompt treatment.^[7] Uncomplicated flu has a shorter course and usually resolves after 3 to 7 days for most people.^[7] For more serious flu complications, the CDC indicates that antiviral drugs can lessen symptoms and shorten duration of sickness by 1 or 2 days.^[10] This is especially important in patients with a higher risk for complications, as those drugs can mean the difference in preventing a hospital stay.^[10] Core prevention studies include administration of influenza vaccine, implementation of respiratory hygiene and cough etiquette, appropriate management of ill healthcare practitioners, adherence to infection control precautions , as well as implementing environmental and engineering infection control measures. ^[10]

In an article published on the World Economic Forum website, Katie Whiting compared coronavirus and the flu.^[11] For the seasonal flu, there is a vaccine to protect against infection.^[11] This cannot be said for 2019-nCoV, for which there is no vaccine.^[11] Research for a vaccine is underway.^[11]

Risk Factors

The risk factors for contracting 2019-nCoV are not yet clear. The CDC estimates that, on average, 8% of the US population gets sick with the flu every year.^[6] This cannot be compared with 2019-nCoV, which is still emerging (12 cases in the United States as of February 10, 2020).^[1] However, healthcare workers are at increased risk for exposure to 2019-nCoV, warns the CDC.^[12]

Older patients and persons with chronic medical conditions may be at higher risk for severe illness when infected.^[3] Nearly all reported cases of the 2019-nCoV infection have occurred in adults (median age, 59 years).

In the study by Li and colleagues^[5], of 425 patients with pneumonia and confirmed 2019-nCoV, infection was in adults age 60 years or older, and 57% were male. Of reported patients, about one-third to one-half had underlying medical comorbidities, including diabetes, hypertension, and cardiovascular disease. Very few of the cases reported have been in children.

Influenza B, which affects young people more severely, has been reported more often this season on a national level, according to the CDC’s most recent flu-surveillance report.^[2] In contrast to the 2019-nCoV, more than half of specimens that tested positive for influenza this season have been in people younger than age 25 years, according to the CDC. They emphasize that anyone can get sick with flu (even healthy people), and serious problems related to flu can happen at any age.^[6] Complications of flu can include bacterial pneumonia, ear infections, sinus infections, and worsening of chronic medical conditions, such as congestive heart failure, asthma, or diabetes.^[6] Some people are at high risk of developing serious flu-related complications if they get sick (ie, age ≥65 years; people of any age with certain chronic medical conditions such as asthma, diabetes, or heart disease; pregnant women and children younger than age 5 years but especially children younger than age 2 years.^[6]

Transmission

In the study by Li et al,^[5] human-to-human transmission was confirmed among close contacts.

With the flu, viruses are spread mainly by droplets through coughing, sneezing, or talking and inhaled into the lungs, according to experts.^[6] People with flu can spread it to others up to about 6 feet away. Less often, a person might get flu by touching a surface or object that has flu virus on it and then touching their own mouth, nose, or possibly their eyes.^[6] The CDC recommends following guidelines to prevent the spread of viruses, such as handwashing, disinfecting surfaces, and avoiding contact with persons who have been infected.^[12]

To conclude, according to the WHO,^[13] differentiating the flu from 2019-nCoV can be difficult through clinical symptoms alone because the symptoms are similar, as is the case with infectious respiratory illnesses. Clinicians need to perform a thorough history and physical examination and perform necessary tests to make a proper diagnosis.

**Studies cited had various limitations, including small sample size, exclusion of suspected but undiagnosed cases, and lack of more detailed patient information and clinical outcomes.

Highlights

• Epidemiology and geography have to play critical roles in the differentiation of influenza from 2019-nCoV. Clinicians need to consider that the only area affected by a broad outbreak of 2019-nCoV is Hubei Province in central China, where 29631 cases have been reported.^[1]
• The CDC currently recommends consideration for evaluation for 2019-nCoV only among patients with fever and cough or shortness of breath who traveled from Hubei Province, China, in the past 14 days or who had close contact with someone with suspected or confirmed infection with 2019-nCoV in the past 14 days. They recently expanded the evaluation recommendation to include anyone traveling from mainland China in the past 14 days with symptoms requiring hospitalization.^[14]
• Symptoms are less discriminatory in comparing 2019-nCoV and influenza. Both viral infections cause fever and cough in the majority of patients affected.
• The duration of symptoms may be more important in distinguishing between infection with 2019-nCoV and influenza. The symptoms of uncomplicated influenza usually last about 3 to 7 days, with gradual improvement in symptoms such as cough up to 2 weeks.^[7]
• In contrast, in a study by Chaolin Huang and colleagues of patients infected with 2019-nCoV, more than half of patients developed dyspnea at a mean of 8 days after the onset of symptoms.^[15]
• Although bilateral patchy infiltrates are present in a minority of chest radiographs of patients with influenza, all patients in the case series infected with 2019-nCoV had abnormal findings on CT.^[15]
• What is understood about the clinical course of 2019-nCoV suggests a more severe infection vs influenza. In the case series, nearly one-third of patients with 2019-nCoV were admitted to the intensive care unit, and 15% died.^[15]
• According to the WHO, differentiating the flu from 2019-nCoV can be difficult through clinical symptoms alone because the symptoms are similar, as is the case with infectious respiratory illnesses. Clinicians need to perform a thorough history and physical examination and perform necessary tests to make a proper diagnosis.^[13]

Clinical Implications

• The current epidemiology of influenza in the United States dwarves the number of infections with 2019-nCoV. The CDC estimates 22 million cases of influenza in the US this flu season, with 210,000 hospitalizations and 12,000 deaths.^[2] Only 319 cases of infection with 2019-nCoV have been detected outside of China (12 cases in the United States) since the outbreak began.^[1]
• Initial symptoms of infection may be the weakest way to differentiate infection with the novel coronavirus vs influenza. Instead, epidemiologic and travel clues can be highly informative, and the course of illness of 2019-nCoV is generally more severe than that of the flu.^[15]
• Implications for the Healthcare Team: The healthcare team should be vigilant for cases of 2019-nCoV while promoting best practices to reduce the effect of influenza on public and individual health.

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