New FDA Warnings for TNF Inhibitors- What are the Fungal Diseases Involved?

Patient Expert

What are the warnings?

The U.S. Food and Drug Administration just announced that the manufacturers of Humira, Cimzia, Enbrel, and Remicade must strengthen the existing "Black Box" warnings because of the risk of developing opportunistic fungal infections. These warnings are located in the Warnings and Precaution sections of the drugs' prescribing information and Medication Guides. The FDA hopes that this new requirement will help health care professionals be more vigilant in watching for these adverse events. The agency also believes the warnings are necessary to ensure that the benefits of these drugs outweigh their risks.

Since the time the FDA first approved each of these medications, the prescribing information for these drugs has included information about the risk of serious infections, including fungal infections. However, over the past several years, there have been several hundred reports of serious fungal infections that were not initially diagnosed, causing delays in treatment. The FDA is concerned that health care professionals are not consistently recognizing cases of histoplasmosis and other invasive fungal infections in a timely manner.

The FDA is requiring the drug manufacturers to submit the safety labeling changes to the FDA within 30 days or to provide a reason why they do not believe labeling changes are necessary. If they do not comply, or if the FDA disagrees with the new language the company proposes, the agency may issue an order directing the labeling change as deemed appropriate to address the new safety information. Medication Guides will become part of a mitigation strategy (called a REMS) for Humira and Remicade and are already part of a REMS for Enbrel and Cimzia. The manufacturers for all four of these drugs will also be required to educate prescribers about the risks.

How many people have been affected?

FDA has reviewed 240 reports of histoplasmosis in patients being treated with Enbrel, Humira, or Remicade. The majority of the reports involved people in the Ohio River and Mississippi River valleys (the fungus is commonly found in those areas). In at least 21 of the reports, histoplasmosis was initially not recognized by health care professionals, and antifungal treatment was delayed. Twelve of those patients died. While it is a relatively small number in comparison to the tens of thousands of people who take TNF inhibitors, it is of great concern to the agency because these serious infections and deaths can be prevented.

The FDA has also reviewed one reported case of histoplasmosis in a patient taking Cimzia and has received reports of cases of coccidioidomycosis and blastomycosis both resulting in several deaths.

What should patients know?

The FDA highlighted some information it believes is important for people on TNF therapy to know. The bullet points are quoted below.

  • Patients treated with TNF blockers have an increased risk for infections. Some patients have had serious infections while receiving TNF blockers. In some cases, patients needed to be hospitalized for treatment. These serious infections include infections caused by viruses, fungi, or bacteria including tuberculosis (TB), including infections that have spread throughout the body. Some patients have died from these infections.
  • If you have weight loss, persistent fever, sweating, cough, shortness of breath, or fatigue, promptly seek medical attention.
  • Tell your doctor where you live and about recent travel in and outside the USA. The risk of some infections is greater in regions where different microorganisms (bacteria, fungi, viruses, parasites) are more common.
  • Tell your doctors that you are taking a TNF blocker. A doctor may make different decisions about your medical treatment if he or she knows that you are taking a TNF blocker. o Tell your doctor about all of your medical conditions, including if you have an infection that won't go away or a history of an infection that keeps coming back.

For more information from the FDA see:

So what are histoplasmosis, coccidioidomycosis and blastomycosis?

The news reports about the new warnings do not really explain in detail what these fungal infections are or where they come from. So the following is basic information about each of these three diseases summarized from information provided by the Centers for Disease Control website.

Overall, there are several commonalities of these three fungal diseases:

  1. All are soil based fungi.

  2. All create spores that become airborne and are breathed in. None are transmitted person to person.

  3. Each is common in a certain part of the country or type of environment.

  4. Each takes one to several weeks for symptoms to appear. Serious cases must be treated with anti-fungal medications or other drugs.

One important note: histoplasmosis and coccidioidomycosis are very common. In areas where they are prevalent, many people may be infected but never show symptoms or the body naturally fights it off easily. It is young children, the elderly, people with chronic lung problems and people with compromised immune systems that are most at risk of actually developing an infection after exposure.

What is histoplasmosis?

Histoplasmosis is a fungal disease that primarily affects the lungs. H. capsulatum grows in soil and material contaminated with bat or bird droppings. It is usually found in poultry house litter, caves, areas harboring bats, and in bird roosts. Spores become airborne when contaminated soil is disturbed and breathing the spores causes infection. The disease is not transmitted from an infected person to someone else.

H. capsulatum is most common in the eastern and central United States, specifically in the Ohio River and Mississippi River areas. Positive histoplasmin skin tests occur in as many as 80% of the people living in these areas. Most infected persons have no apparent ill effects, but infants, young children, and older persons, in particular those with chronic lung disease are at increased risk for severe disease. People who take a job or activity having a risk for exposure to H. capsulatum should read the NIOSH/NCID Document Histoplasmosis: Protecting Workers at Risk, which contains information on work practices and personal protective equipment that will reduce the risk of infection.

In rarer cases, histoplasmosis affects other organs (a form called disseminated histoplasmosis) and this can be fatal if untreated. This disseminated form is more frequently seen in people with cancer, AIDS or other forms of immunosuppression.

Symptoms of histoplasmosis include: respiratory symptoms, a general ill feeling, fever, chest pains, and a dry or nonproductive cough. Distinct patterns may be seen on a chest x-ray. Chronic lung disease resembles tuberculosis and can worsen over months or years. If symptoms occur, they usually present within about 10 days after exposure, but may present within 3 to 17 days.

Acute histoplasmosis and all cases of chronic and disseminated disease are treated with antifungal medications. Mild disease usually resolves without treatment. A person can be infected more than once, but past infection usually results in partial protection from future infections. Past infection results in partial protection against ill effects if reinfected.

What is coccidioidomycosis?

Coccidioidomycosis, also known as Valley Fever, is a fungal disease caused by the Coccidioides species of organisms that live in the soil of semiarid areas. It is very common in the southwestern United States, parts of Mexico and South America. It is a reportable disease in states where the disease is endemic, such as California, New Mexico, Arizona and Nevada. 10-50% of all people who live in one of these regions will have evidence of exposure to Coccidioides.

Most people who get the disease either live in or visit places where the fungus is in the soil and engage in activities that expose them to dust (such as construction, agricultural work, military field training or archeological exploration). People of African-American, Asian or Filipino descent appear to be at increased risk. So are pregnant women during the third trimester and immunocompromised persons.

Fungal spores that become airborne after disturbance of contaminated soil by humans or natural disasters (e.g., dust storms and earthquakes) and like histoplasmosis, infection occurs from breathing in the spores. It is not spread from person to person or from animals to people.

Symptoms may appear between 1-3 weeks after exposure. About 60% of infections do not cause any symptoms; however, symptoms include flu-like illness, fever, cough, headache, rash and muscle aches. A doctor diagnoses the infection by testing blood or other body fluid to look for antibodies against the fungus. Or a biopsy or culture of affected tissue may be performed and the tissue is examined under a microscope to look for the fungus.

Most people make a full recovery, within weeks to months of symptom onset, sometimes without any treatment, but a small number of people may develop chronic pulmonary infection or widespread disseminated infection. If the infection spreads outside of the lungs, it can cause skin lesions, central nervous system infections, such as meningitis, and bone and joint infections. Doctors may prescribe antifungal drugs to treat patients with acute, uncomplicated coccidioidomycosis, but these drugs are necessary to treat people with more severe infections. Antibacterial drugs do not treat coccidioidomycosis.

People who live in an endemic area, such as Arizona or Southern California may contact their local or state health department for the most up-to-date information about outbreaks, particularly following earthquakes or other events that disturb large amounts of soil.

What is blastomycosis?

Blastomycosis caused by the fungus, Blastomyces dermatitidis. This fungus is found in parts of the south-central, south-eastern and mid-western United States and in Central and South America and parts of Africa. The fungus is found in moist soil with decomposing organic debris, like farms and wooded areas. Like the previous two fungal diseases, the infection is spread by inhalation of airborne spores after disturbance of contaminated soil. It is not transmitted from person to person. People at most risk of developing the disease are those who engage in work or recreational activities in such areas (e.g., farmers, forestry workers, hunters, and campers).

About 50% of infected people show symptoms of the disease, and when they do, symptoms generally appear between 3 and 15 weeks after exposure. These include a flu-like illness with fever, chills, productive cough, myalgia, arthralgia and pleuritic chest pain. Some patients develop chronic pulmonary infection or widespread disseminated infection (affecting the skin, bones and genitourinary tract in particular) or an infection of the central nervous system, resulting in meningitis. Blastomycosis must be treated with antifungal drugs. If untreated, the infection can lead to complications and death.