Invasive Fungal Infections: A Creeping Public Health Threat
Fungal infections most often present themselves as minor annoyances: a gross toenail, itchy ringworm, or perhaps a more pesky mucosal infection such as thrush in the mouth and vaginal yeast infections. These superficial infections affect an estimated 15% of the world’s population and can present meaningful lifestyle hurdles, but are rarely life threatening. However, invasive fungal infections are collectively responsible for killing up to 1.5 million people each year, making this infection category one of the most deadly among communicable diseases, along with lower respiratory infections, tuberculosis and diarrheal diseases.
Despite the high mortality rates of invasive fungal infections (upwards of 50%), experts estimate that 80% of those patients might be saved with appropriate diagnostics and treatments. But diagnosing fungal infections is difficult, in part because of their nonspecific symptoms. Many patients are misdiagnosed with bacterial and/or viral infections, delaying appropriate treatment. Fungi are also rapidly becoming resistant to the current arsenal of antifungal agents. Improvements are needed to make progress in these areas, but the question remains: why have fungal infections become more frequent?
Fungal infections were considered rare until the mid-20th century. They were considered diseases of the “immunocompromised and the unlucky,” a statement that succinctly describes the two types of fungal pathogens, opportunistic and primary. Opportunistic fungi only cause invasive infections in those who are immunodeficient, while primary fungi are those capable of causing invasive disease in healthy individuals. Increased numbers of invasive infections by both groups of fungal pathogens have been fueled with technological advances that improved medical care and led to increasing global travel.
Increasing Opportunities for Opportunistic Fungi
In the mid-to-late 1900s, significant medical advances began extending and improving the lives of many people with previously fatal health conditions, such as liver failure, cancer and premature birth. But organ transplants, chemotherapy and radiation result in patients that are immunocompromised for brief or extended periods of time. An increasing immunocompromised patient population, as well as the spread of human immunodeficiency virus (HIV) in the 1980s, has greatly increased the incidence of fatal fungal infections around the world. Infections by Candida spp. yeasts (common members of the human microbiome) account for 50–60% of all fungal infections following organ transplants, and together, four fungal infections (cryptococcal meningitis, pneumocystis pneumonia, disseminated histoplasmosis and chronic pulmonary aspergillosis) account for nearly 50% of all AIDS-related deaths.
For instance, Pneumocystis jirovecii pneumonia (PCP), a previously rare disease, became a defining diagnosis for HIV/AIDS patients, reaching a global incidence rate of 4.9 per 100 person-years in 1995. With the introduction of anti-HIV therapies, the incidence rate of PCP dropped to 0.3 per 100 person-years in just three years (1998), though it remained the most common opportunistic infection in the U.S. from 2008 - 2010. More recently, Cryptococcus neoformans was estimated to cause more than 1 million cases of meningitis and more than 600,000 deaths in 2009, primarily in HIV-positive patients, though experts expect that number to have dropped as a result of increased screening and improved medical therapies. Unfortunately, in 2016, an estimated 16.7 million HIV-positive individuals didn’t have access to anti-HIV therapies, putting them at increased risk of invasive fungal infections.
Patients undergoing surgery, chemotherapy or other invasive procedures are given prophylactic treatments to prevent infections. Although this strategy helps prevent bacterial and viral infections, it can also increase a patient’s susceptibility to fungal infections. For example, patients undergoing bone marrow transplants are often prescribed the antiviral ganciclovir for 4 or more weeks to prevent cytomegalovirus infections. Unfortunately, ganciclovir use also correlates with invasive aspergillosis; each additional week of use (past week 4), increases the infection risk by 40%. Similarly, anti-yeast treatments increase the risk of mycelial infections (such as aspergillosis) from 18 to 29%.
Aspergillus spp. can cause pneumonia, invasive disease and a progressive allergic lung disease, particularly in asthmatics and those with cystic fibrosis. A French study examining a national hospital database found a 4.4% yearly increase in invasive aspergillosis from 2001– 2010. Similar increases have been reported in other studies. Aspergillosis infections have a high mortality rate of about 50% with timely diagnosis and treatment on time, otherwise the mortality rate is 80%.
While the fungi discussed above are the most common opportunistic fungal infections in immunocompromised patients, these may only be a drop in the bucket compared to the total number of potential opportunistic fungi. One expert suggests that more than 400 different fungal species may be responsible for opportunistic infections, though most may have only been encountered once or twice. Regardless of the infecting fungal species, the increasing number of patients living with compromised immune systems, whether because of age, HIV status, cancer or organ transplants, has contributed to the increasing number of invasive fungal infections.
The Spread of Primary Fungal Pathogens
Primary fungal pathogens include species such as Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioidis immitis, Paracoccidioidis brasiliensis and Penicillium marneffei. Interestingly, many of these primary fungal pathogens alter their cell shape (or morphology) during human infection, switching between circular yeast and elongated hyphae based on either temperature or host-associated molecules.
Most thermally dimorphic fungi grow in the soil as branching mycelial networks up to 25ºC. If disturbed and inhaled into the lungs, the hyphae convert to single-cell yeasts at the higher temperature (37ºC) to cause pneumonia and disseminate through the bloodstream. Thermal dimorphs can infect both healthy and immunocompromised humans, as well as other mammals (e.g., dogs, cats and armadillos) and include the fungal species that cause blastomycosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis and sporotrichosis.
The transition to the yeast morphology is accompanied by the up-regulation of a suite of virulence factors that promote adhesion, growth in and lysis of macrophages, and to impair the immune response. Non-thermally dimorphic fungi, on the other hand, tend to infect plants and insects, with the transition between forms triggered by oxygen levels, nitrogen sources, pheromones and quorum-sensing molecules.
Many of these primary fungal pathogens have historically held to geographic boundaries, with species endemic to particular areas. For instance, the thermal dimorph H. capsulatum is the most common transplant-related endemic mycosis in the U.S., with the Midwest recording 6.1 cases per 100,000 person-years between 1999–2008. It is also the most common opportunistic infection of HIV-positive patients in Latin America. But histoplasmosis has now been described in China, India, Central and Western Africa, and Madagascar.
While the mycelial survival and growth of H. capsulatum (and other thermal dimorphs) in the soil contributes to some migration, it certainly doesn’t explain crossing entire oceans. Humans routinely do so, however. Not only has increasing global travel allowed endemic fungi to spread wherever humans and their property may go, but climate change has increased the area where traveling fungi may successfully take root. Both of these factors increase the number of people who might be counted as “unlucky.”
Unfortunately, when it comes to combating the increasing number of invasive fungal infections, we’re fighting an uphill battle. In addition to problematic diagnostics and treatments, getting a true picture of the global burden of invasive fungal infections is difficult because surveillance is almost nonexistent for many fungal infections in many parts of the globe. Even in the U.S., the most widely reportable fungal infection is coccidioidomycosis (also known as Valley fever, the incidence rate of which has increased from 5.3 per 100,000 people years in 1993 to 42.6 in 2011), and it is only reported by 23 states. The lack of reliable data complicates (and delays) coordinated responses to an increasing public health threat.