Fungal Infections and Antimicrobial Resistance Rates: Part 2

This article is the second part of two-part coverage on a study conducted by Rutgers University researchers that analyzes the effects of misdiagnosing fungal infections on the increasing rates of antimicrobial resistance.

Chronic Pulmonary Aspergillosis Misdiagnosed as Tuberculosis

According to a 2008 study, patients with smear-negative pulmonary tuberculosis (TB) are often less infectious than those who are smear-positive. Smear-negative cases refer to patients who are diagnosed with TB despite not being infected. The researchers recognize that those who are misdiagnosed with TB may actually have chronic pulmonary aspergillosis (CPA), a condition that mimics the effects of TB. They note that in a study out of the United Kingdom involving 544 patients who had been treated for TB, 134 went on to develop precipitating antibodies to Aspergillus fumigatus within 2 years; within 5 years, 34% of the total patient population had developed precipitating antibodies to Aspergillus fumigatus. Of the 134 patients, 58% (78) went on to develop late stage CPA within 2 years. However, the researchers report that “few prospective studies have been conducted on CPA after treatment for TB, so the incidence of such cases cannot be stated with certainty; conservatively, however, a rate of ≈10% among survivors of pulmonary TB is likely and a global prevalence of ≈1.2 million cases is probable.”

The researchers warn that culture testing smear-negative patients for Myobacterium tuberculosis is slow and may yield false negatives. They recommend testing respiratory specimens through DNA detection assays, although this method is also not 100% accurate. Among smear-negative patients, many have relapsed after receiving treatment for TB, while many of those cured of TB have developed CPA. The researchers also warn that death rates in HIV patients are higher among those with smear-negative pulmonary TB as opposed to those with smear-positive. They state, “It is increasingly recognized that many of these patients are chronically infected with Aspergillus spp., resulting in CPA that is largely undiagnosed and untreated.”

The researchers then go on to state that signs and symptoms as well as chest radiographs are similar in both TB and CPA patients. They also note that CPA is a common complication associated with TB infection, and that the associated life expectancy among CPA patients has a “5-year death rate of 75%-80%.” Thus, it is recommended to actively test for CPA in patients who already completed antimicrobial therapies for TB but are still presenting with symptoms.

To properly diagnose CPA infection, the researchers recommend using Aspergillus antibody detection, which has 96%-97% sensitivity and 92%-98% specificity. Citing two studies with high rates of fungal infections in patients thought to be infected with TB, the researchers concluded, “This finding and the recognition of patients with pulmonary histoplasmosis or coccidioidomycosis indicate that other, potentially treatable diseases, not smear-negative TB, may be responsible for illness attributed to TB.”

The researchers then go on to state that it is “unnecessary” to empirically treat patients with fungal infections, such as CPA, for TB, citing that it is “ineffective” and harmful. When TB treatment does not seem to show any signs of alleviating infection, physicians frequently believe that the patient has drug-resistant TB, utilizing second- and third-line TB medications, note the researchers. This not only increases the economic burden on patients, it also leads to an increased risk of drug resistance.

Chronic Obstructive Pulmonary Disease and Fungal Asthma

Fungal asthma is defined by the researchers to be “asthma exacerbated by fungal sensitization, airways fungal colonization asthma, and/or allergic bronchopulmonary aspergillosis complicating asthma.”

The researchers recognize that chronic obstructive pulmonary disease (COPD) is most often treated with antibiotics; however, they advise against the “unnecessary” use of antibiotics in COPD patients “in the absence of purulent sputum and pulmonary infiltrates.” They cite a study out of Spain in which 1.3% of patients who were admitted to a hospital due to COPD were, in fact, later infected with aspergillosis. Of those patients, 65% died. Similarly, data from China reveal that 3.9% (≈462,000 patients of ≈11,858,000 total) of those hospitalized with COPD had aspergillosis, and 43% (≈200,000 patients of ≈462,000 total) died. Since these data rely on Aspergillus sputum cultures, these numbers “are probably underestimated,” according to the Rutgers researchers, adding that patients are not often treated for aspergillosis, but they do receive antibiotics unnecessarily.

Fungal asthma is frequently misdiagnosed as COPD. The researchers believe that early diagnosis along with treatment using antifungal medications can substantially reduce the rate of hospitalization and misused antibiotics; furthermore, long-term therapy with antifungals has been successful in treating fungal exacerbations in 60%-80% of patients who have asthma.

The researchers recommend total and fungal-specific IgE testing to properly diagnose fungal asthma. Furthermore, although not many studies have investigated how fungus can affect precipitating exacerbations of COPD, they believe that chronic and invasive aspergillosis can be diagnosed using either culture, antigen, or Aspergillus spp. IgG testing.

The researchers attribute the steadily increasing misuse of antibiotics among patients with asthma and COPD who are also infected with Aspergillus spp. to failure to properly diagnose these patients. They conclude, “Recognition of fungal infection and allergy and treatment with directed antifungal therapy would greatly reduce exacerbations, medical consultations, and hospital admissions.”

Fungal Infections and Improving Antimicrobial Stewardship

The authors recognize that there are multiple other clinical scenarios where proper timely diagnosis of fungal infections can not only reduce the economic burden of these infections, but can also improve antimicrobial prescribing and reduce the rate of drug resistance. Ultimately, they believe that nonculture fungal diagnostic tools can increase the rates of identifying fungal infections. They concluded that, “the lack of availability and underuse of nonculture fungal diagnostics results in overprescribing, prescription of unduly long courses of antibacterial agents, and excess empirical use of antifungal agents and leaves many millions of patients with undiagnosed fungal infections.”

Read Part 1 of this article here.