The Deadliest Epidemics in United States History

Masked families and a masked pet during the Great Influenza pandemic, in California, c. 1918-1920.

Did you know that dogs and cats donned masks during the Great Influenza? Or that Alexander Hamilton fled Philadelphia in 1793 to escape Yellow Fever? Or that scientists have found smallpox pustules on the mummy of an ancient Egyptian Pharaoh? As the world confronts the devastating spread of Covid-19, we look back to previous epidemics to understand their grave impacts and the lessons we’ve learned. We also examine the way everyday people learned to adapt, coexist, and persevere among these severely frightening historical moments.

How much do you know about historical pandemics? Here are the most significant facts and surprising trivia of the deadliest outbreaks in U.S. history:


  • COVID-19 is a new and emerging infectious disease with ongoing outbreaks that continue to threaten the health of people in the United States and worldwide.
  • Although the disease can infect and kill anyone, the majority of infected young people tend to remain asymptomatic and never develop the illness. Whereas, older infected adults often develop either a mild case or serious illness, which requires hospitalization and can quickly lead to death.
  • Spread of this new strain of the novel coronavirus occurs when a person is exposed to an infected person’s respiratory droplets through close contact.
  • Infected people often appear healthy in the asymptomatic phase of the disease for 2-14 days after exposure to COVID-19, during which time they could be unknowingly spreading the disease.
  • The most common symptoms of this highly contagious virus includes fever, cough, fatigue, and shortness of breath which typically presents 2-14 days after being exposed.
  • The first confirmed case of COVID-19 was identified in Wuhan, Hubei Province, China, in November 2019.
  • In January 2020, the first documented case in the U.S. was confirmed in Washington state. The man had just returned from a trip to Wuhan.
  • The CDC recommends wearing a mask, social distancing, and washing hands frequently to lower the risk of contracting the disease.
  • There is no known cure to date.
  • Click here for up-to-date case totals in the U.S. and worldwide.


  • HIV stands for human immunodeficiency virus which can lead to AIDS, or acquired immunodeficiency syndrome.
  • HIV is caused by a retrovirus, which attacks the body’s immune system leaving its victim more susceptible to potentially fatal infections.
  • A type of chimpanzee from Central Africa has been identified as the source of HIV. The virus may have mutated and infected humans as a result of hunting practices as far back as the late 1800s.
  • In 1981, the virus was first officially identified in the U.S. after it started spreading through the gay community.
  • HIV is typically spread through body fluids during sex or needle sharing with other people.
  • The chances of an HIV-positive person infecting another person increases the higher their viral load.
  • One of the first drugs, AZT, that was developed to treat AIDS caused side effects that half the patients could not tolerate.
  • There is no cure for the disease, but more infected people are living longer due to educational outreach and advances in modern medicine.
  • Preventative measures include abstinence, using condoms, and avoiding the sharing of needles. Prevention medicines include prophylaxis (PrEP) and post-exposure prophylaxis (PEP).
  • Approximately 32 million people have died of AIDS worldwide since the HIV virus was first identified.
  • Although AIDS was first identified in 1981, President Reagan failed to address the epidemic in a constructive way. His first notable mention of the crisis was in a 1985 press conference when he shared his doubts in allowing children with AIDS to continue to attend school. It was not until 1987, after thousands had already died of the disease, did his chilling silence end by recommending equal doses of medicine and morality to tackle the illness.


  • Polio, or poliomyelitis, is a crippling viral infection that affects the spinal cord which can lead to chronic shortness of breath, permanent paralysis, and death in humans.
  • The virus, which can be traced back to ancient Egypt, spreads through fecal matter and contaminated food and water that is ingested.
  • Milder symptoms of the disease can plague a person years later—causing joint pain, chronic fatigue, and muscle weakness.
  • Young people under five years old are most vulnerable to catching the disease. After exposure, some caught a severe form of the disease while most had mild symptoms and fully recovered.
  • In the U.S. alone, polio outbreaks caused approximately 15,000 cases of paralysis every year prior to the mid-20th century.
  • Polio was eventually eradicated in the U.S. after the introduction of the poliovirus vaccine (IPV), developed by Jonas Salk in the early 1950s. By the 1970s, there were fewer than 10 cases recorded.

The Great Influenza

The Spanish Flu
  • The 1918 influenza pandemic was the most lethal disease in recent U.S. history.
  • Since most people did not have immunity to this H1N1 virus, as many as 20,000 Americans died each week.
  • In the United States, this strain of flu first infiltrated military personnel in Kansas, then spread east with the troops during World War I.
  • The mortality rate was high in young, healthy people; including the 20-40 years old, which are unusual casualties during common flu epidemics that typically kills the older population.
  • By the time the disease ran its course in 1920, it killed approximately 675,000 U.S. citizens and a staggering 50-100 million people worldwide.
  • Although commonly referred to as the Spanish Flu, there is no consensus on where it originated. The name stuck because Spain devoted so much coverage to the outbreaks.
  • While in pursuit of a cure, scientists incorrectly assumed the flu was caused by bacteria instead of a virus during the time.
  • At the height of the pandemic, U.S. officials encouraged citizens to wear face masks to prevent spread of infection. Many were distributed by the Red Cross or made at home using gauze or handkerchiefs.


  • Cholera is an illness caused by the bacteria V. cholerae that attaches to the intestines causing severe diarrhea, dehydration, and death.
  • The bacterium can be transmitted from person to person.
  • This disease is most often contracted from infected human skin, untreated sewage, and through contaminated food and drinking water.
  • Cholera was documented as early as 2,500 years ago.
  • In 1832, a new wave of immigrants crossing the Atlantic brought cholera to North America.
  • Up until the late 1800s, many doctors did not believe the disease was contagious.
  • The bacterium was not discovered until the last half of the 19th century by Italian anatomist Filippo Pacini, and then by German bacteriologist Robert Koch who made subsequent advancements in Pacini’s discovery.
  • After the link between sanitation and cholera was established, New York City created a board of health to manage the disease in 1870.
  • Public health improved when the city alleviated poor sanitation and quarantined those exposed to cholera.
  • The last major outbreak in the U.S. occurred in New York City after infected people from Italy arrived by steamship in 1910.

Typhoid Fever

Mary Mallon
  • Typhoid fever is caused by Salmonella serotype Typhi and Salmonella serotype Paratyphi.
  • The bacteria is treated with antibiotics.
  • The disease spreads through impure water, tainted food, and human waste.
  • Symptoms of the disease include red marks on the skin, upset stomach, headache, and high fever.
  • In the early 1900s, the disease sickened approximately 3,467 people and killed 639 in New York City. The bacteria was lethal because antibiotics to treat it were not discovered until decades later.
  • Although typhoid fever is rare today, approximately 350 people are diagnosed with the illness in the United States each year.
  • Mary Mallon was nicknamed “Typhoid Mary” after infecting several New York households with the illness, in 1906. A total of 53 people were infected and 3 died due to her poor food-handling practices. When authorities finally tracked down the cook, she reluctantly tested for the disease with positive results. However, she refused to stop working as a cook and continued to knowingly expose other unsuspecting victims. Finally, Mallon was arrested and forced to quarantine for several years by court order—only to resurface again years later and sicken more people after her release.

Yellow Fever

Yellow Fever
  • A yellow fever epidemic devasted Philadelphia, in August 1793.
  • The invisible plague was brought to the New England town by war refugees from the Caribbean.
  • Because doctors were unaware of the existence of viruses and bacteria at the time, fatalities surged as officials argued about how to best treat and eradicate the disease.
  • Many health care workers and politicians, including infected Alexander Hamilton and his wife, fled the City of Brotherly Love to escape the epidemic.
  • By the time yellow fever finally started to slow with the arrival of cold weather the following October, the virus had claimed the lives of approximately 6,000 men, women, and children.
  • Sporadic outbreaks continued over the next 100 years in the Eastern United States, killing thousands more until 1905 when the last major outbreak of the scourge concluded in the U.S.
  • Tree-living monkeys in Africa and South America were the most likely source of the virus.
  • Mosquitoes are carriers of yellow fever.
  • Although there is now a vaccine against yellow fever, there is no cure.


  • Smallpox, or the variola virus, has plagued humans with random outbreaks for thousands of years. It was commonly spread on trade routes throughout Asia, Europe, and Africa.
  • Smallpox is one of the most feared diseases because of its disfiguring rash which can leave permanent scars and cause blindness. Highly contagious, it has a 3 percent death rate.
  • Europeans first brought the disease to the New World via the slave trade in the 16th century, killing many indigenous peoples in America.
  • In colonial America, Benjamin Franklin’s son died of the virus when he was only 4 years old, in 1736. This founding father advocated for the distribution of pamphlets to the colonists instructing them on how to inoculate their children at home.
  • Dating back to China as early as the 15th century, this inoculation method called “Variolation” exposed healthy people to the mild form of the virus before they acquired it naturally. They would either rub their arm or inhale ground smallpox scabs from a smallpox patient. This treatment protected people from dying of a more severe form of the disease.
  • Scientific advancements perfected a smallpox vaccine, resulting in the eradication of natural outbreaks in the U.S. since 1949 and worldwide since 1977.
  • Scientists found traces of smallpox pustules on the head of a mummy thought to be Pharaoh Ramses V, who reigned in Egypt, during the 3rd century BCE.
  • Other early cases of the disease described as smallpox were documented in China during the 4th century and in India during the 7th century.

All of these examples show that diseases have flourished as long as human beings have congregated for survival. Often insidious, highly contagious viruses and bacteria can easily spread silently and swiftly through human populations. These deadly epidemics usually hit cities first and often claim the most vulnerable among us; generally, the socio-economically disadvantaged and immune compromised are impacted the most. Eventually, many of these infectious diseases disappear as mysteriously as they arrived, but not before wreaking immeasurable havoc—indiscriminately leaving destroyed economies and lives in their wake.