Diphtheria: Symptoms, Causes & Vaccine Protection

What Is Diphtheria and How Does It Spread?

Diphtheria is a serious bacterial infection caused by Corynebacterium diphtheriae that produces a toxin affecting the throat, heart, and nervous system. It spreads through respiratory droplets when an infected person coughs or sneezes, or through direct contact with infected skin lesions. The incubation period is typically 2-5 days.

Diphtheria has been one of the most feared childhood diseases throughout history. Before the introduction of vaccination in the 1920s, diphtheria caused devastating epidemics, killing tens of thousands of children annually in the United States alone. The disease was so prevalent and deadly that it earned the name "the strangling angel of children" because of its ability to suffocate victims through the membrane that forms in the throat.

The bacterium Corynebacterium diphtheriae produces a powerful exotoxin that is responsible for the disease's most serious effects. This toxin inhibits protein synthesis in cells, leading to tissue death and the formation of the characteristic pseudomembrane in the respiratory tract. The toxin can also spread through the bloodstream, causing damage to distant organs including the heart muscle and peripheral nerves.

Understanding how diphtheria spreads is essential for prevention. The primary mode of transmission is through respiratory droplets expelled when an infected person coughs, sneezes, or even speaks. These droplets can travel up to 6 feet and infect anyone who inhales them. Additionally, diphtheria can spread through direct contact with discharge from skin lesions in cases of cutaneous (skin) diphtheria, which is more common in tropical regions and among people with poor hygiene conditions.

Types of Diphtheria

There are two main clinical forms of diphtheria, each with distinct characteristics and implications:

Respiratory diphtheria is the more common and serious form. It primarily affects the throat and tonsils, but can also involve the nose, larynx (voice box), and lower respiratory tract. The toxin produced by the bacteria causes local tissue necrosis, resulting in the formation of a thick, adherent pseudomembrane. This membrane is grayish-white in color and bleeds when attempts are made to remove it. In severe cases, the membrane can extend to cover the entire pharynx and even the trachea, leading to life-threatening airway obstruction.

Cutaneous diphtheria affects the skin rather than the respiratory tract. It typically presents as non-healing ulcers with a gray membrane covering. While cutaneous diphtheria is generally less severe than respiratory diphtheria, it serves as an important reservoir for the bacteria and can transmit infection to others. This form is more prevalent in tropical climates and in populations with limited access to hygiene and healthcare.

Why Is Diphtheria Still a Concern Today?

Despite the remarkable success of vaccination programs, diphtheria has not been eradicated and remains a public health concern for several reasons. Outbreaks continue to occur in regions with low vaccination coverage, including parts of Africa, South Asia, and the former Soviet Union, where political and economic disruptions led to major outbreaks in the 1990s. Additionally, waning immunity in adults who have not received booster doses creates pockets of susceptibility even in countries with high childhood vaccination rates.

Travel to endemic areas poses a risk for unvaccinated or under-vaccinated individuals. The global interconnectedness of modern society means that imported cases can occur anywhere. Furthermore, the emergence of antimicrobial resistance, although not yet a major problem with diphtheria, could potentially complicate treatment in the future.

What Are the Symptoms of Diphtheria?

The main symptoms of diphtheria include sore throat, mild fever (38-39°C), swollen neck glands (bull neck), difficulty swallowing, and a thick gray-white membrane covering the throat and tonsils. This membrane is the hallmark sign of diphtheria and can cause breathing difficulties if it extends to obstruct the airway. Symptoms typically appear 2-5 days after exposure.

Diphtheria symptoms develop gradually, usually beginning 2 to 5 days after exposure to the bacteria. The initial symptoms may resemble those of a common cold or sore throat, which can lead to delayed diagnosis. However, as the disease progresses, the characteristic features become more apparent. Recognizing these symptoms early is crucial because treatment must begin immediately to prevent serious complications.

The early phase of diphtheria typically begins with general malaise, mild fever, and a sore throat. Patients often experience fatigue, loss of appetite, and a low-grade fever, usually not exceeding 39°C (102°F). The sore throat gradually worsens over the following days. Unlike streptococcal pharyngitis (strep throat), the throat pain in diphtheria is usually moderate rather than severe, despite the extensive involvement of the tissues.

The development of the pseudomembrane marks the transition to the more serious phase of the disease. This thick, gray-white coating typically appears on the tonsils and posterior pharynx within 2 to 3 days of symptom onset. The membrane is composed of dead tissue, bacteria, fibrin, and white blood cells. It is firmly attached to the underlying tissues and bleeds when removal is attempted. The membrane may extend to cover the soft palate, uvula, and even the nasal passages or larynx.

Characteristic Signs of Diphtheria

Several distinctive features help differentiate diphtheria from other causes of sore throat:

• The pseudomembrane: The thick, adherent gray-white membrane is the most characteristic finding. Unlike the white patches seen in strep throat or thrush, this membrane is firmly attached and bleeds when disturbed.
• Bull neck appearance: Severe swelling of the lymph nodes in the neck, combined with soft tissue edema, creates a distinctive bull neck appearance that indicates serious infection.
• Foul breath odor: A distinctive, unpleasant odor is often present due to tissue necrosis and bacterial activity.
• Nasal discharge: When the nose is involved, patients may have bloody nasal discharge or crusting around the nostrils.

Symptoms of Laryngeal Diphtheria

When diphtheria involves the larynx (voice box) and trachea, additional symptoms develop that indicate a potentially life-threatening situation. Hoarseness or voice changes are early signs of laryngeal involvement. As the membrane extends to cover the larynx, patients develop stridor (a high-pitched breathing sound) and increasing difficulty breathing. Cyanosis (blue discoloration of the lips and skin) indicates severe respiratory compromise requiring immediate intervention.

Laryngeal diphtheria was historically the most feared form of the disease because it could rapidly progress to complete airway obstruction and death. Even today, with modern medical care, patients with severe laryngeal involvement may require emergency tracheostomy or intubation to maintain a patent airway.

What Complications Can Diphtheria Cause?

Diphtheria can cause serious, life-threatening complications due to the toxin spreading through the bloodstream. The most dangerous complications are myocarditis (heart muscle inflammation) occurring in 10-25% of cases, peripheral neuropathy (nerve damage) causing paralysis, and airway obstruction from the membrane. These complications can occur even weeks after the initial infection resolves.

The complications of diphtheria result primarily from the powerful exotoxin produced by Corynebacterium diphtheriae. This toxin enters the bloodstream and can damage cells throughout the body, with the heart and nervous system being particularly vulnerable. Understanding these complications is essential because they can develop even after the throat infection has improved, sometimes weeks after the acute illness.

The severity of complications correlates with several factors, including the extent of local disease, the delay before treatment initiation, and the patient's age and overall health status. Patients with extensive membrane formation and those who receive antitoxin more than 48 hours after symptom onset have significantly higher rates of complications and death.

Cardiac Complications

Myocarditis (inflammation of the heart muscle) is the most serious complication of diphtheria and the leading cause of death in affected patients. It occurs in approximately 10-25% of diphtheria cases and can develop at any time during the first 2-3 weeks of illness, most commonly during the second week. The diphtheria toxin directly damages heart muscle cells, disrupting their ability to conduct electrical impulses and contract effectively.

Symptoms of myocarditis include rapid or irregular heartbeat, chest pain, shortness of breath, and in severe cases, signs of heart failure such as swelling of the legs and difficulty breathing when lying flat. Patients with diphtheria require careful cardiac monitoring, as myocarditis can progress rapidly to life-threatening arrhythmias or complete heart block. Some patients may require temporary pacemaker insertion or treatment for heart failure.

The prognosis for diphtheric myocarditis varies widely. Mild cases may resolve completely, while severe cases can result in permanent heart damage or death. The mortality rate for patients who develop myocarditis is approximately 50-60%, making early prevention through vaccination crucially important.

Neurological Complications

Peripheral neuropathy is another serious complication of diphtheria, occurring in approximately 5-10% of cases. The toxin damages the myelin sheath (protective covering) of peripheral nerves, disrupting nerve signal transmission. Neurological complications typically develop 2-8 weeks after the onset of infection, often after the patient has otherwise recovered from the acute illness.

The neurological manifestations follow a characteristic pattern. The earliest finding is usually palatal paralysis, which causes difficulty swallowing and a nasal quality to the voice. This may be followed by weakness of the eye muscles, leading to blurred vision and difficulty focusing. In more severe cases, generalized weakness affecting the limbs and respiratory muscles can develop, sometimes resembling Guillain-Barré syndrome.

Unlike the cardiac complications, neurological damage from diphtheria is usually reversible, although recovery may take weeks to months. Complete resolution is the rule for most patients, but severe cases requiring prolonged ventilatory support may have residual deficits.

Respiratory Complications

Airway obstruction from the extending pseudomembrane remains a life-threatening complication, particularly in young children whose airways are smaller. The membrane can detach and be aspirated (inhaled) into the lower airways, causing sudden respiratory obstruction. Secondary bacterial pneumonia can also occur, adding to the respiratory compromise.

How Is Diphtheria Diagnosed?

Diphtheria is diagnosed based on clinical presentation (sore throat with gray membrane) and confirmed by throat culture identifying Corynebacterium diphtheriae. The Elek test determines if the bacteria produce toxin. However, treatment must begin immediately based on clinical suspicion without waiting for laboratory confirmation, as delays significantly increase mortality.

The diagnosis of diphtheria is primarily clinical, meaning that doctors must recognize the characteristic features of the disease and begin treatment immediately without waiting for laboratory confirmation. This approach is essential because the case fatality rate increases dramatically with each day of delayed antitoxin treatment. Laboratory tests serve to confirm the diagnosis and identify cases that might not be clinically obvious.

Clinical diagnosis relies on recognizing the combination of sore throat, low-grade fever, and the characteristic pseudomembrane covering the tonsils and posterior pharynx. The membrane's appearance is distinctive: it is gray-white to greenish, thick, and firmly adherent to the underlying tissues. Attempts to remove the membrane cause bleeding, which helps differentiate it from the easily removable white patches seen in other conditions such as streptococcal pharyngitis or candidiasis (thrush).

Laboratory Confirmation

Several laboratory tests are used to confirm diphtheria:

Throat culture is the gold standard for diagnosing diphtheria. Swabs should be taken from beneath the membrane edges or from the nasopharynx. The specimens are cultured on special selective media (tellurite blood agar or Loeffler's medium) that allow Corynebacterium diphtheriae to grow while inhibiting other bacteria. Results typically take 24-48 hours. It is important to inform the laboratory of suspected diphtheria, as routine throat cultures may not include the appropriate media.

The Elek test (modified toxigenicity test) determines whether the isolated Corynebacterium diphtheriae strain produces toxin. This is clinically important because not all strains of the bacterium produce toxin, and only toxin-producing strains cause the severe systemic effects of diphtheria. PCR (polymerase chain reaction) testing for the toxin gene can provide faster results than the traditional Elek test.

Additional tests may include complete blood count (which often shows elevated white blood cells), kidney function tests, and cardiac enzyme levels to assess for myocarditis. An electrocardiogram (ECG) and echocardiogram are typically performed to evaluate heart function, as cardiac complications are common and serious.

How Is Diphtheria Treated?

Diphtheria treatment requires immediate hospitalization with two main components: diphtheria antitoxin to neutralize circulating toxin, and antibiotics (penicillin or erythromycin for 14 days) to kill the bacteria. Treatment must begin immediately upon clinical suspicion without waiting for laboratory confirmation. Supportive care includes airway management and cardiac monitoring.

The treatment of diphtheria is a medical emergency that requires prompt hospitalization, preferably in an intensive care unit where continuous monitoring is available. The two pillars of treatment are diphtheria antitoxin, which neutralizes the toxin before it can bind to cells, and antibiotics, which eliminate the bacteria and prevent further toxin production. Supportive care, including airway management and cardiac monitoring, is equally critical for patient survival.

Time is of the essence in diphtheria treatment. The antitoxin can only neutralize toxin that is circulating in the blood—once the toxin has bound to cells, it cannot be reversed. Studies have shown that mortality increases dramatically with each day of delayed treatment: patients who receive antitoxin within the first 24 hours of symptoms have mortality rates of about 1%, while those treated after 4 days have mortality rates exceeding 20%.

Diphtheria Antitoxin

Diphtheria antitoxin (DAT) is the specific treatment that neutralizes the diphtheria toxin. It is produced from the serum of horses that have been immunized against diphtheria toxin. Because of its equine origin, there is a risk of allergic reactions, including anaphylaxis and serum sickness. Skin testing for hypersensitivity should be performed before administration, but treatment should not be withheld even if skin testing cannot be done.

The dose of antitoxin depends on the extent and duration of disease. Patients with localized pharyngeal disease of less than 48 hours duration may receive 20,000-40,000 units, while those with extensive disease or delayed presentation may require 80,000-120,000 units. The antitoxin is given intravenously or intramuscularly, with intravenous administration preferred for severe cases.

Antibiotic Therapy

Antibiotics are essential to eliminate the bacteria and prevent further toxin production. The recommended antibiotics are:

• Penicillin G (intravenous or intramuscular) or penicillin V (oral) for 14 days
• Erythromycin for patients allergic to penicillin, also for 14 days

Antibiotic treatment also reduces transmission to others by eliminating the bacteria from the throat. Patients remain infectious until two consecutive throat cultures taken 24 hours apart are negative, typically achieved after about 48 hours of antibiotic therapy.

Supportive Care

Supportive care is critical and includes:

• Airway management: Close monitoring for airway obstruction is essential. Patients with severe laryngeal involvement may require intubation or tracheostomy.
• Cardiac monitoring: Continuous ECG monitoring detects arrhythmias early. Bed rest is recommended for 2-3 weeks to reduce cardiac workload.
• Isolation: Respiratory isolation prevents transmission to healthcare workers and other patients.
• Nutritional support: Patients with difficulty swallowing may require nasogastric feeding or intravenous nutrition.

How Can Diphtheria Be Prevented?

Diphtheria is prevented through vaccination with DTaP (for children) or Tdap (for adolescents and adults). The vaccine is approximately 95% effective after completing the primary series. Children receive 5 doses by age 6, and adults need booster doses every 10 years to maintain immunity. Vaccination has reduced diphtheria cases by over 99% since its introduction.

Vaccination is by far the most effective method of preventing diphtheria. The development and widespread use of the diphtheria toxoid vaccine is one of the greatest public health achievements of the 20th century. Before vaccination became available, diphtheria was a leading cause of childhood death in developed countries. Today, thanks to routine childhood immunization, the disease is rare in most of the world.

The diphtheria vaccine contains diphtheria toxoid—a chemically inactivated form of the diphtheria toxin that stimulates the immune system to produce protective antibodies without causing disease. The vaccine does not contain live bacteria and cannot cause diphtheria. It is always given in combination with other vaccines, most commonly tetanus toxoid and pertussis vaccine.

Recommended Vaccination Schedule

The vaccination schedule varies by age:

For infants and children (DTaP vaccine):

• 2 months of age: First dose
• 4 months of age: Second dose
• 6 months of age: Third dose
• 15-18 months of age: Fourth dose (booster)
• 4-6 years of age: Fifth dose (booster before school entry)

For adolescents and adults (Tdap/Td vaccines):

• 11-12 years of age: Tdap booster
• Every 10 years thereafter: Td (tetanus-diphtheria) or Tdap booster
• Pregnant women: One dose of Tdap during each pregnancy (preferably weeks 27-36)

Post-Exposure Prophylaxis

People who have been in close contact with a confirmed diphtheria case require prophylactic measures regardless of their vaccination status:

• Surveillance: Daily monitoring for symptoms for 7 days after last contact
• Throat cultures: To identify carriers who may transmit the disease
• Prophylactic antibiotics: Erythromycin or penicillin for 7-10 days
• Vaccination update: Booster dose if more than 5 years since last vaccination, or completion of primary series if never vaccinated

Where Is Diphtheria Still a Problem?

Diphtheria remains endemic in parts of Africa, South Asia (especially India, Indonesia, Bangladesh), and some Eastern European countries. The disease has been largely eliminated in countries with high vaccination coverage, but outbreaks can occur when vaccination rates decline. Worldwide, approximately 5,000-7,000 cases are reported annually, though actual numbers may be higher due to underreporting.

The global distribution of diphtheria reflects the success of vaccination programs in different regions. In countries where childhood vaccination coverage exceeds 90%, diphtheria has become extremely rare. However, the disease continues to cause significant morbidity and mortality in parts of the world where vaccination coverage is inadequate or has declined due to social, political, or economic disruptions.

The epidemiology of diphtheria demonstrates both the power of vaccines and the consequences of letting vaccination coverage decline. The large-scale outbreak in the former Soviet Union during the 1990s, which caused over 150,000 cases and 5,000 deaths, occurred following the collapse of the Soviet healthcare system and the disruption of vaccination programs. This outbreak served as a stark reminder that diphtheria can rapidly return when population immunity wanes.

Current Endemic Regions

Diphtheria remains endemic or causes regular outbreaks in several regions:

• South Asia: India, Indonesia, Bangladesh, and Nepal report the majority of global cases. India alone accounts for approximately 60-70% of reported cases worldwide.
• Sub-Saharan Africa: Several African countries report cases, particularly in areas with low vaccination coverage and limited healthcare access.
• Middle East: Yemen, affected by ongoing conflict, has experienced significant outbreaks in recent years.
• South America: Venezuela has seen outbreaks associated with economic crisis and healthcare system collapse.
• Eastern Europe: While the 1990s epidemic has been controlled, some countries continue to report sporadic cases.

Risk Factors for Outbreaks

Several factors contribute to diphtheria outbreaks:

• Low vaccination coverage: The most important factor—when immunization rates fall below 80-85%, outbreaks become more likely.
• Population displacement: Refugees and internally displaced persons often have incomplete vaccination and live in crowded conditions.
• Healthcare system disruption: Conflict, economic collapse, and natural disasters can interrupt vaccination programs.
• Adult susceptibility: Even in well-vaccinated populations, adults who have not received boosters may lose immunity over time.

What Is the History of Diphtheria?

Diphtheria has been recognized since ancient times and was one of the most feared childhood diseases until vaccination became available in the 1920s. The development of diphtheria antitoxin in the 1890s was one of the first successful applications of immunology to medicine, and the subsequent diphtheria vaccine transformed this deadly disease into a rare occurrence in vaccinated populations.

The history of diphtheria is a remarkable story of scientific discovery, medical innovation, and public health triumph. For centuries, diphtheria was one of the leading causes of childhood death, striking fear into parents and communities alike. The development of effective treatments and eventually a vaccine represents one of medicine's greatest achievements.

Diphtheria was described in ancient texts from Egypt, Greece, and Syria, where physicians noted the characteristic membrane in the throat and the disease's often fatal outcome. The name "diphtheria" comes from the Greek word for leather, referring to the tough, leathery appearance of the pseudomembrane. Major epidemics swept through Europe periodically, with particularly devastating outbreaks in the 17th and 18th centuries.

Scientific Breakthroughs

Several key discoveries led to the control of diphtheria:

1883: Edwin Klebs identified the bacterium, and a year later, Friedrich Loeffler proved it was the cause of diphtheria. The bacterium was subsequently named Corynebacterium diphtheriae, also known as the Klebs-Loeffler bacillus.

1888: Émile Roux and Alexandre Yersin at the Pasteur Institute demonstrated that the disease's effects were due to a toxin produced by the bacteria, not the bacteria themselves.

1890: Emil von Behring and Shibasaburo Kitasato developed diphtheria antitoxin by immunizing animals and harvesting their serum. This was one of the first applications of passive immunization and earned von Behring the first Nobel Prize in Physiology or Medicine in 1901.

1913: Béla Schick developed the Schick test to determine susceptibility to diphtheria, enabling targeted immunization.

1923: Gaston Ramon developed diphtheria toxoid, the inactivated form of the toxin used in modern vaccines. Mass vaccination programs began shortly thereafter.

Impact of Vaccination

The introduction of widespread vaccination transformed diphtheria from a common killer to a rare disease. In the United States, diphtheria caused approximately 200,000 cases and 15,000 deaths annually in the early 1920s. By the 1970s, fewer than 10 cases were reported per year. Similar dramatic declines occurred in all countries that implemented routine childhood vaccination.

The 1925 serum run to Nome, Alaska—commemorated by the Iditarod sled dog race—illustrated both the deadly threat of diphtheria and the life-saving importance of antitoxin. When a diphtheria outbreak threatened the isolated town, a relay of sled dog teams transported antitoxin across 674 miles of frozen wilderness, saving the community from a devastating epidemic.