Fungal infections are common and usually treatable. But they can be deadly in patients with immune systems compromised by diseases such as AIDS or by meds taken to keep them in check when they become too active (causing so-called autoimmune conditions such as lupus and rheumatoid arthritis), or to prevent rejection of organ transplants.
Now drug regulators say a class of medicines called TNF alpha blockers such as Enbrel, Remicade, Humira and Cimzia must carry stronger warnings that they pose a serious risk of histoplasmosis infection, a respiratory or blood illness caused by fungi endemic to the Midwest. Yesterday's announcement by the U.S. Food and Drug Administration (FDA) primarily affects patients with inflammatory disorders, including rheumatoid arthritis and Crohn's disease, who are typically prescribed TNF inhibitors to reduce symptoms. The drugmakers say they're working to comply with the order.
We asked L. Joseph Wheat to explain histoplasmosis and two similar infections, coccidioidomycosis and blastomycosis, that the FDA says are also linked to TNF blockers. Wheat, founder of MiraVista Diagnostics and MiraBella Technologies, developed a test for histoplasmosis. He also served as a consultant to a biotech company after a patient receiving the company's experimental gene therapy died of histoplasmosis.
What is a fungal infection?
A fungus is a class of microorganism that may cause infections. This FDA alert involves a group called endemic micoses: the histo, blasto and cocci grow in the soil, and when the soil is disturbed, spores are released into the air and patients and animals inhale them. Histo and cocci show up in areas of the country where the fungus is endemic; in those places, up to 70 percent of residents have had these infections at some point in their lives. Histo and blasto are common in the Midwest U.S., the Ohio and Mississippi River Valley, around the Great Lakes and in parts of Canada. Cocci are most common in the southwestern U.S., the San Joaquin Valley in California and in Arizona, and as far east as Texas and as far north as Utah.
What is histoplasmosis? What about the others -- coccidioidomycosis and blastomycosis?
All three are acquired by inhalation and are somewhat similar. They cause a lung infection that would behave like pneumonia and can spread from the lungs to the bloodstream that would lead to a generalized infection. Cocci and blasto more commonly involve skin and bone, so there are some differences, but there probably are more similarities.
Who gets these infections?
Among healthy people who live in areas where the fungi are endemic, over half will have had these infections by age 20, but in healthy individuals, it's either asymptomatic and they don’t even know they had it, or it's mild enough that it never makes it to their doctors' attention. If the exposure is more intense -- if someone is working in the soil -- the infection even in a healthy individual may be more severe, as a pneumonia that impacts breathing and results in hospitalization. But usually they recover with or without treatment.
Those with more severe infections are usually immuno-compromised with AIDS, organ transplants or other immuno-deficient states, and that’s where this warning came out. They're more severe in babies, because they haven’t developed normal immunity, and in the elderly, because immunity declines with aging. They are more likely to have a severe infection and have it spread to other areas of the body.
A patient with cancer wouldn't develop these infections unless they're receiving chemotherapy that would predispose them to it. But they are common in lymphoma patients because that disease suppresses immunity.
What are the symptoms?
In patients who are immune suppressed, two thirds have respiratory complaints like cough or shortness of breath. The other third wouldn’t have a respiratory component and would just have weight loss, fatigue and fevers. They may also have skin sores or bone sores or brain involvement, sores in the mouth or intestines. The manifestation is quite variable and can involve almost any organ in the body.
It could be silent or may not cause severe enough symptoms or symptoms that are different than those they are already receiving treatment for, so it takes a while before the patient and doctor realize something is going on other than the underlying disease. One of the big problems has been that physicians haven’t thought about these infections when patients have symptoms, so they haven't thought to order tests or diagnose it.
Why would these infections kill someone? Because it isn’t caught in time?
These infections would in 90 percent of cases be fatal if they're not treated in people with AIDS, organ transplants or who are on TNF blockers. The speed of illness could vary from death within three weeks of the onset of symptoms, to an infection of a year or more.
What are TNF alpha blockers? Who takes them, and why might they increase the risk of contracting a fungal infection?
Tumor necrosis factor is a protein that's released from blood cells that causes inflammation and enhances the ability of blood cells to fight infection. TNF is also involved in symptoms in inflammatory disorders like ulcerative colitis, Crohn's disease and rheumatoid arthritis.
Usually these patients already are receiving corticosteroids and methotrexate to manage the disorder. The TNF inhibitor is prescribed to reduce the effects of TNF in a patient's inflammatory response, so patients with inflammatory disorders not controlled by traditional immunosuppressants improve markedly with TNF inhibitors.
But TNF also kills those fungi. So while inhibiting TNF leads to improvement in the inflammatory disorder, if a patient has one of these infections, the drug can lead to worsening of the infection because TNF is involved in controlling the infection.
Do other drugs also increase the risk of these infections?
Almost any immunosuppressive medication -- corticosteroids, prednisone, cortisone, methotrexate for Psoriasis and rheumatoid arthritis -- would. So would anti-thymocyte globulin taken by organ transplant recipients to prevent or treat rejection.
What can patients do to minimize their risk of serious infection?
The first step is for a doctor to be aware of the risk and order tests for these infections. There are a number of tests, including a biopsy where you could see the organism in the tissue, and that could give a rapid diagnosis. There also is an antigen-detection system to pick up the fungi in the blood or urine. Both tests could give a result in 24 to 48 hours.
The third option would be a culture of the tissue, but it can take a month in histoplasmosis to get a positive result. Serology, which measures antibody response, can be helpful, but it often shows a negative result because patients are immunosuppressed and can't make antibodies.
How are these infections treated?
Patients diagnosed before they're severely ill are treated with antifungals, including amphtericin D and another group of oral medications called triazoles, including itraconazole, fluconazole, voriconazole and posaconazole. If patients are ill enough to be hospitalized, they'd begin with amphetericin D and later with an oral triazole. If it's a mild case, they may not be hospitalized, but would be treated with one of the triazoles. These treatments are over 90 percent effective if the patient is not severely ill with the infection. If they are severely ill, there is a 50 percent mortality rate.