By Philip R. Fischer, MD, DTM&H

Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN

Dr. Fischer reports no financial relationships relevant to this field of study.

SYNOPSIS: Histoplasmosis is increasingly seen beyond the previous risk areas of the Ohio and Mississippi River valleys. Diagnostic and treatment practices vary widely.

SOURCE: Benedict K, Beer KD, Jackson BR. Histoplasmosis-related healthcare use, diagnosis, and treatment in a commercially insured population, United States. Clin Infect Dis 2019; Apr 30. doi: 10.1093/cid/ciz324. [Epub ahead of print].

Histoplasmosis is an infection caused by inhalation of an environmental fungus. In the United States, it has been thought to primarily occur in the Ohio and Mississippi River valleys. A range of presentations occur, from asymptomatic infection to fatal disseminated disease, and risk factors for severe illness in immunocompromised patients have been described. However, Benedict and colleagues from the Centers for Disease Control and Prevention sought to characterize histoplasmosis among the general population. Realizing that diagnostic and management practices vary widely, they sought to characterize just how American physicians care for patients with histoplasmosis.

The researchers obtained information from a 2011-2015 database of individual insurance claims resulting from ambulatory and inpatient services provided to more than 230 million insured people (employees, family members of employees, and retired employees) in the United States. Patients with histoplasmosis were identified using billing codes. Of more than 85 million active enrollees in the database, there were 8,169 with a coded diagnosis of histoplasmosis during the years 2012 to 2014. Of these, 3,625 had pre-diagnosis data to determine care for symptomatic illness prior to the establishment of a new histoplasmosis diagnosis. From these, patients were included in the study if prescription data were available, leaving a total of 1,935 subjects available for full analysis.

Rigorously analyzing data, researchers found that about half of the subjects were thought to be “probable” cases of histoplasmosis, and the other half were “suspect” cases (since they had only one outpatient visit related to the diagnosis and no inpatient care or follow-up visit). Probable cases were more likely to be male (51% vs. 45%), younger (median 55 years vs. 58 years), and immunocompromised (24% vs. 13%). Of the total, 44% lived in the east north central region of the United States.

Analysis of pre-histoplasmosis diagnostic codes revealed that 54% of subjects had received medical care during the three months prior to the histoplasmosis diagnosis for respiratory symptoms or signs that could have been due to histoplasmosis. The median time between the initial visit with concerning findings and the ultimate histoplasmosis diagnosis was 45 days. Azithromycin and amoxicillin were given commonly for the respiratory illness prior to the diagnosis of histoplasmosis.

Along the way toward the histoplasmosis diagnosis, only 33% of patients received a Histoplasma-specific antigen or antibody test. Overall, 44% had tissue analysis (biopsy or cytopathology). Immunocompromised patients were more likely to undergo Histoplasma-specific testing. Interestingly, 13% received the diagnosis of histoplasmosis without any laboratory testing and with no associated symptoms or signs of infection, and they received no antifungal treatment.

Treatment varied, with 29% receiving outpatient antifungal treatment. The duration of treatment was longer in immunocompromised than in immunocompetent patients (median 238 days vs. 98 days).

Of study subjects, 19% were hospitalized for histoplasmosis. Of the total cohort of subjects, 3% died while hospitalized.

The authors highlighted the wide spectrum of illness severity in patients with histoplasmosis, the infrequency of specific fungal testing, and the seeming delay in diagnosis for many patients. They also emphasized the fact that more than one-third of the patients with histoplasmosis in this national database resided outside of the geographic areas usually associated with the infection.

COMMENTARY

Even though this study was just a review of insurance claims data and did not include chart reviews by medical experts, the authors managed to uncover valuable information. We who are aware of this study now might need to broaden our geographic suspicion for histoplasmosis, increasingly consider conducting specific Histoplasma testing, and seek more standardized care plans.

Many of us have relegated concern for histoplasmosis to people who have contact with soil near the Mississippi and Ohio River valleys. Although these new data do not rule out travel through these areas as a means of infection for those residing elsewhere, the fact that less than half of the individuals identified as infected lived in an area of risk suggests that the transmission of histoplasmosis is probably occurring well beyond the Ohio and Mississippi River valleys. As noted in an editorial accompanying the paper, the “times have changed,” and it is “time to redraw the map” of where histoplasmosis occurs.1 Perhaps related to climate change and altered living patterns of bats and starlings (who deposit Histoplasma-laden “fertilizer” in soil), the endemic area for histoplasmosis is spreading north and west of the Ohio and Mississippi River valleys, with some patients becoming infected even much farther away.1 At the same time, travelers who visit caves in Central America also are at risk of becoming infected.2 Histoplasmosis also is increasingly recognized in people living with HIV and AIDS elsewhere in the Americas, such as in Brazil.3

It is hard to judge a population incidence of histoplasmosis from insurance data in a select population of employed individuals. However, the data in this study would suggest that the incidence of histoplasmosis in the general population is in the range of “one in a million.” Bacterial and viral causes of respiratory infection are much more common. However, histoplasmosis should not be ignored, especially with severely ill individuals. When the diagnosis is considered, Histoplasma-specific antibody or antigen testing could be considered; this was not the case for two-thirds of the subjects in the Benedict et al study. Interestingly, the most recent (2007) histoplasmosis management guidelines from the Infectious Diseases Society of America did not mention diagnostic testing.4

With improving HIV management and with increasing solid organ transplantation, HIV-infected patients accounted for only 11% of the immunocompromised patients in this study. The others had immune-mediated inflammatory disease, a hematologic malignancy, or a transplant. Whatever their immunocompromising condition, immunocompromised patients with respiratory symptoms should raise concern for histoplasmosis.

Benedict et al conducted their study when the 2007 Infectious Diseases Society of America’s histoplasmosis treatment guidelines were established but still recent. Many patients do not need antifungal treatment. However, as noted in the editorial accompanying the Benedict paper, when treatment is given, more than one-third of patients received a non-preferred regimen.1 When dealing with conditions that we do not treat often, physicians should seriously consider following standard guidelines for the good of their patients.

REFERENCES

  1. McKinsey DS, Pappas PG. Histoplasmosis: Time to redraw the map and up our game. Clin Infect Dis 2019; Apr 30. doi: 10.1093/cid/ciz327. [Epub ahead of print].
  2. Staffolani S, Buonfrate D, Angheben A, et al. Acute histoplasmosis in immunocompetent travelers: A systematic review of literature. BMC Infect Dis 2018;18:673.
  3. Falci DR, Monteiro AA, Braz Caurio CF, et al. Histoplasmosis, an underdiagnosed disease affecting people living with HIV/AIDS in Brazil: Results of a multicenter prospective cohort study using both classical mycology tests and Histoplasma urine antigen detection. Open Forum Infect Dis 2019;6:ofz073.
  4. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007;45:807-825.