Understanding Influenza: Lessons from a Century of Pandemic Response

Table of Contents

• Case Presentation: The 24-Year-Old Man
• Physical Examination and Findings
• Differential Diagnosis
• The 1918 Influenza Pandemic
• Discovering the Influenza Virus
• Developing the First Vaccines
• Influenza Surveillance Systems
• The 1957 Asian Flu Pandemic
• The 1968 Hong Kong Flu Pandemic
• The 2009 Swine Flu Pandemic
• Current State of Influenza Protection
• Implications for Future Pandemics
• Source Information

Case Presentation: The 24-Year-Old Man

In March 1923, a previously healthy 24-year-old man arrived at Massachusetts General Hospital with severe respiratory symptoms. His illness began three days earlier with malaise (general weakness and discomfort), generalized weakness, headache, and back pain. Over the next two days, his symptoms persisted, and he remained mostly bedridden.

The day before admission, he developed fever, dry cough, and severe chills that caused him to shake violently and curl into a fetal position. He took aspirin at a dose of 10 grains (648 mg) every 4 hours, which provided some relief for his headache and back pain. On the day of admission, he awoke with difficulty breathing and chest pain just below the xiphoid process (the bottom tip of the breastbone), which worsened with deep breathing and coughing.

Physical Examination and Findings

On examination, the patient had a high rectal temperature ranging from 39.5°C to 40.8°C (103.1°F to 105.4°F), an elevated heart rate between 92 and 145 beats per minute, and a rapid respiratory rate of 28 to 58 breaths per minute. He appeared acutely ill, nervous, and was shivering despite being wrapped in multiple blankets.

His breathing was rapid, shallow, and labored with frequent episodes of racking cough that produced pinkish, thick, slightly purulent (pus-containing) sputum. The cough caused excruciating pain under his lower sternum (breastbone).

Examination revealed:

• Heart sounds were rapid and regular with a soft systolic murmur at the apex
• Breath sounds were diminished on the right side of the back from the lower scapula downward
• No evidence of rales (abnormal lung sounds) or friction rub
• White blood cell count ranged from 3,700 to 14,500 per microliter with 79% neutrophils (a type of white blood cell that fights infection)
• Blood cultures showed no bacterial growth

A chest radiograph showed bilateral patchy consolidations (areas of dense lung tissue), most confluent in the right upper lobe and left lower lobe, suggesting pneumonia. There was also fullness in the left hilar region (where airways and blood vessels enter the lungs), possibly indicating lymphadenopathy (swollen lymph nodes).

Despite treatment, the patient's condition deteriorated over four days. His sputum became more purulent, and increased dullness was noted on percussion of the left lower back. He gradually grew weaker and died on the fourth hospital day.

Differential Diagnosis

Medical experts analyzing this case concluded the patient likely had influenza, possibly complicated by bacterial superinfection causing pneumonia and possible empyema (pus collection in the space between lungs and chest wall). The presentation occurred just five years after the devastating 1918 influenza pandemic, making influenza the most likely diagnosis.

The case serves as a window into understanding how far we've come in diagnosing, treating, and preventing influenza over the past century.

The 1918 Influenza Pandemic

The 1918 influenza pandemic, often called the "Spanish flu," actually began in the United States. The first case was diagnosed in a U.S. Army cook at Fort Riley, Kansas, on March 4, 1918. Shortly after, a physician named Loring Miner in Haskell County, Kansas, diagnosed 18 cases of severe influenza, including 3 deaths.

Unfortunately, during World War I, the U.S. government was not transparent about the outbreak's severity. As historian John Barry noted, "The government lied. They lied about everything... They simply didn't tell the people the truth about what was happening." Since Spain was neutral in the war and published openly about the disease, it became known as the "Spanish flu" despite originating in the U.S.

The pandemic was devastating:

• 300,000 Americans died from September-December 1918 alone
• This death toll was 10 times higher than from any cause during the same period in 1915
• Over 500 million people worldwide were affected
• An estimated 100 million people died globally

Treatment options were extremely limited in 1918, consisting mainly of aspirin and opium. The only intervention with any success was transfusion of blood from recovered patients to newly infected patients—what we now call convalescent plasma therapy.

Discovering the Influenza Virus

For years, the causative agent of the "Spanish flu" was incorrectly thought to be Pfeiffer's bacillus (now known as Haemophilus influenzae). This bacteria was found in the sputum of many—but not all—affected patients, and its absence was attributed to being difficult to culture.

The actual influenza virus was finally identified in 1933 by Wilson Smith and colleagues. They obtained throat washings from people with influenza, passed them through a bacteria-impermeable membrane, and exposed ferrets to the sterile filtrate. The ferrets developed influenza-like symptoms within two days.

Interestingly, one of Smith's colleagues, Charles Stuart-Harris, accidentally contracted influenza after an infected ferret "sneezed violently at close range." The virus isolated from Stuart-Harris was then used to infect a previously uninfected ferret, demonstrating transmission.

Developing the First Vaccines

Once the influenza virus was identified, work began on vaccine development. In 1936, Frank Macfarlane Burnet discovered that the influenza virus grew easily in fertilized hen eggs—a production method still used today.

The first influenza vaccine was developed in 1940 by Thomas Francis and Jonas Salk. Given influenza's devastating impact on the military during World War I, U.S. Army soldiers were the first to be vaccinated in the early 1940s. By 1942, evidence showed vaccination provided protection, and the first influenza vaccine was approved for civilian use in 1946.

Vaccination proved highly effective—the incidence of influenza among unvaccinated people was 10 to 25 times higher than among vaccinated individuals.

Influenza Surveillance Systems

As vaccines developed, surveillance systems became critically important for tracking influenza activity and guiding public health responses. The U.S. Centers for Disease Control and Prevention (CDC) established its first influenza surveillance system in 1954.

The World Health Organization (WHO) formed the Global Influenza Surveillance and Response System in 1952. This collaboration now includes 144 national influenza centers in over 114 countries that conduct year-round surveillance.

Today, the CDC's influenza surveillance rests on four pillars:

1. Laboratory testing (100 public health laboratories and 300 clinical laboratories)
2. Monitoring outpatient cases (3,400 providers reporting on 100 million patient visits)
3. Tracking hospitalizations (covering 9% of the U.S. population through the FluSurv-NET system)
4. Recording deaths (through death certificate data and pediatric mortality surveillance)

The 1957 Asian Flu Pandemic

The 1957 influenza pandemic originated in southern China in early 1957. The new virus subtype (influenza A virus subtype H2N2) resulted from a mutation in an avian influenza strain in wild ducks that recombined with a human influenza strain.

China was not yet part of the WHO and didn't inform the rest of the world about the outbreak. The warning came from U.S. microbiologist Maurice Hilleman, who read about thousands of cases in Hong Kong in the New York Times in April 1957. After acquiring a virus sample from U.S. Navy doctors in Japan, Hilleman identified the strain and warned of a potential pandemic.

The virus reached the U.S. in June 1957 through infected military personnel returning from Asia. The pandemic had two waves:

• First wave (October 1957): Mostly affected school-age children
• Second wave: More heavily affected older adults with higher mortality

The U.S. response was limited—only 30 million people were vaccinated (approximately 18% of the population). Despite this limited vaccination, the 1957 pandemic caused:

• 20 million documented infections in the U.S.
• 116,000 U.S. deaths
• 1-4 million deaths worldwide

It's estimated that the available vaccine before the February 1958 spike saved over 1 million U.S. lives.

The 1968 Hong Kong Flu Pandemic

The 1968 influenza pandemic began in China in July 1968. Within two weeks, 500,000 cases had been documented in Hong Kong. The new virus subtype (influenza A virus subtype H3N2) resulted from a genetic mutation that facilitated human-to-human transmission.

Fortunately, there was enough similarity to previous influenza strains that prior exposure offered partial protection. Although highly transmissible, the "Hong Kong flu" caused milder illness than the 1918 and 1957 pandemics.

The pandemic resulted in:

• 1 million deaths worldwide
• 100,000 deaths in the U.S., mostly among older adults

A monovalent vaccine became available, but only after the pandemic peak.

The 2009 Swine Flu Pandemic

The 2009 influenza pandemic began in Mexico in March 2009, with the first death occurring there in April. The new virus subtype (influenza A virus subtype H1N1) was a triple reassortment from bird, swine, and human viruses, initially called "swine flu."

The global impact included:

• 700 million to 1.4 billion people affected worldwide
• 284,000 estimated excess deaths
• 60 million U.S. cases
• 274,000 U.S. hospitalizations
• 12,500 estimated U.S. deaths

Although 41% of the U.S. population received the seasonal influenza vaccine that year, it didn't protect against H1N1. The monovalent H1N1 vaccine became available in October 2009, around the time U.S. cases peaked. Only 27% of the U.S. population received this targeted vaccine, though approximately 40% of school-age children were vaccinated through school vaccination programs.

Current State of Influenza Protection

Today, influenza vaccines are created by the WHO twice per year. Over the past 20 years, average reported effectiveness has ranged from 40% to 55%. Vaccination coverage varies significantly:

• Approximately 50% of the U.S. population gets vaccinated annually
• Nearly 75% of people over 65 years are vaccinated each year
• Almost 50% of people with health insurance are vaccinated
• Only 15% of uninsured people receive influenza vaccination

The Vaccines for Children program has successfully closed this gap for pediatric populations. A similar Vaccines for Adults program has been proposed in the President's budget to assist over 25 million uninsured adults, but this program has yet to be funded.

During the COVID-19 pandemic, the CDC developed the Respiratory Virus Hospitalization Surveillance Network (RESP-NET) dashboard to track COVID-19, influenza, and respiratory syncytial virus infections. However, now that the COVID-19 public health emergency has ended, the CDC lacks authority to compel reporting of hospitalization data—reporting to the National Healthcare Safety Network is voluntary.

Implications for Future Pandemics

Remarkable scientific progress has been made since the 1918 influenza pandemic. We've identified the virus, developed vaccines, and created surveillance systems that provide earlier warnings of potential pandemics. However, significant challenges remain:

Political will and social contracts have stagnated since 1918. Surveillance data are reported voluntarily without bipartisan commitment to standardize reporting. There's often insufficient community commitment to take actions that protect others. Communication challenges foster fearmongering, controversy, and misinformation.

As John Barry wrote, "Society cannot function if it's every man for himself. By definition, civilization cannot survive that." The diagnosis for our country is this: despite tremendous scientific advances, little progress has been made in addressing the social challenges that limit the impact of our scholarly progress.

Failing to learn from previous pandemics has left us with fractured health care, public health, and vaccine distribution systems. While significant strides were made in recognizing these fractures during COVID-19, we must leverage these lessons for future pandemic preparedness.

Source Information

Original Article Title: Case 27-2024: A 24-Year-Old Man with Pain and Dyspnea

Authors: Rochelle P. Walensky, Meridale V. Baggett, Kathy M. Tran, Jo-Anne O. Shepard, David M. Dudzinski, Dennis C. Sgroi

Publication: The New England Journal of Medicine, September 5, 2024

DOI: 10.1056/NEJMcpc2402491

This patient-friendly article is based on peer-reviewed research from The New England Journal of Medicine.