MAJOR ARTICLE

Coccidioidomycosis in Patients with HIV-1 Infection in the Era of Potent Antiretroviral Therapy
Fares Y. Masannat and Neil M. Ampel
Division of Infectious Diseases, Department of Medicine, and the Valley Fever Center for Excellence, University of Arizona, and the Southern Arizona Veterans Affairs Health Care System, Tucson

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Background. Coccidioidomycosis is a common opportunistic infection in human immunodeciency virus type 1 (HIV-1)infected individuals living in regions where coccidioidomycosis is endemic. However, there have been no studies on its incidence or clinical expression during the era of potent antiretroviral therapy. Methods. Clinical data were abstracted from the records of all HIV-1infected patients attending a single clinic in a region where coccidioidomycosis is endemic from January 2003 through May 2008. Additional follow-up was performed through May 2009 for individuals with active coccidioidomycosis. A case-control study was performed that compared all individuals who attended the clinic with individuals who received a diagnosis of coccidioidomycosis. Results. Among 257 HIV-1infected patients seen over a 64-month period, 29 cases (11.3%) of coccidioidomycosis were identied. Twelve patients (4.7%) received a diagnosis of coccidioidomycosis during the study period (annual incidence, 0.9%). Patients with less severe coccidioidomycosis were signicantly more likely to have an undetectable HIV RNA level and to be receiving potent antiretroviral therapy than were those with more severe disease (for both, P ! .01 ). Five patients with coccidioidomycosis received no antifungal therapy, and 11 others had antifungal therapy discontinued. All were healthy during follow-up. Patients with coccidioidomycosis had signicantly lower CD4 T lymphocyte counts than did control subjects (mean standard deviation, 285 42 cells/mL vs 477 21 cells/mL; P p .003). Conclusions. The incidence of symptomatic coccidioidomycosis in the era of potent antiretroviral therapy has decreased, and its clinical expression is less severe than it was before the potent antiretroviral therapy era. Severity of coccidioidomycosis was inversely associated with control of HIV-1 infection. Within a few years after the initial description of AIDS, reports of cases in association with coccidioidomycosis surfaced [13]. In these publications, coccidioidomycosis was noted to be severe, overwhelming, and often directly associated with death. Although the clinical spectrum of coccidioidomycosis during human immunodeciency virus type 1 (HIV-1) infection was subsequently more completely dened, infection was still associated with substantial morbidity and mortality among patients with HIV-1 infection [46]. Beginning around 1996, the use of 3 antiretroviral agents concomitantly was recommended for the treatment of HIV-1 infection. Use of this potent antiretroviral therapy (ART) resulted not only in a reduced progression of HIV-1 disease [7], but also in a decrease in the morbidity and mortality associated with AIDS [8]an observation which has been recently validated [9]. This decrease occurred in association with a marked decrease in the number of opportunistic infections [10]. These observations prompted changes in the recommendations for the prevention and management of such HIV-1associated infections [11]. Unfortunately, studies examining the incidence of coccidioidomycosis during HIV-1 infection have predated or only slightly overlapped the potent ART era. A prospective study conducted from 1988 through 1992 in a single HIV-1 clinic located in a region where coccidioidomycosis is endemic demonstrated that nearly 25% of the cohort developed clinically active coccidioidomycosis after 41 months of follow-up [12]. In that study, of 13 individuals who developed active coccidioidomycosis, 5 presented with diffuse pulmonary disCoccidioidomycosis in the Potent ART Era CID 2010:50 (1 January) 1

Received 24 June 2009; accepted 17 August 2009; electronically published 8 December 2009. Reprints or correspondence: Dr Neil M. Ampel, Medical Service (1111), SAVAHCS, 3601 S Sixth Ave, Tucson, AZ 85723 (nampel@email.arizona.edu). Clinical Infectious Diseases 2010; 50:17 2009 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2010/5001-0001$15.00 DOI: 10.1086/648719

Table 1. Clinical Parameters by Type of Presentation in 29 Patients with Active Coccidioidomycosis

No. of patients with an HIV RNA level !50 copies/mL 3/5 5/5 0/6 0/6 No. of patients receiving potent ART/total no. of patients 4/5 6/6 3/5 0/4 0/1 No. of patients receiving antifungal therapy/total no. of patients 4/8 5/7 6/8 4/4 2/2 No. of patients who survived/total no. of patients 8/8 7/7 7/8 3/4 2/2

Type of presentation Positive serological test result Nodule and/or cavity Focal pulmonary Diffuse pulmonary Disseminated

Median CD4 T lymphocyte count, cells/mL 444 320 206 55

Median log IDCF titer 1:2 1:2

!1:2

1:4

NOTE. Data on median CD4 T lymphocyte count, plasma (human immunodeciency virus) HIV RNA level, complement xation (IDCF) titer, and receipt of potent antiretroviral therapy (ART) are from the time of diagnosis of coccidioidomycosis. Data on antifungal therapy and survival are from the follow-up period.

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ease, 4 had focal pulmonary alveolar inltrates, 2 had pulmonary nodules, and 1 had a positive serological test result only. An additional patient presented with extrathoracic dissemination. Five died during the follow-up period. Using reports from state health departments obtained from 1987 through 1992, Jones et al [13] revealed that 8.2% of patients with AIDS in Arizona had disseminated coccidioidomycosis. In the only study, to our knowledge, during the potent ART era, Woods et al [14] used data from the Arizona Department of Health from 1995 through 1997. They identied 77 cases of coccidioidomycosis in patients with HIV-1 infection in 1995, compared with only 15 cases in 1997, suggesting that potent ART had an impact on the number of cases. To more completely ascertain the effect of potent ART on the incidence and clinical manifestations of coccidioidomycosis in a region where coccidioidomycosis is endemic, we recently retrospectively reviewed our experience in the same clinic where the aforementioned original prospective study was performed [12]. Our current data suggest a marked decrease in the incidence and severity of coccidioidomycosis during the potent ART era.

MATERIALS AND METHODS Computerized records of patients attending the HIV Clinic at the Southern Arizona Veterans Affairs Health Care System (Tucson, AZ) were reviewed from January 2003 through May 2008. Follow-up analysis was done through May 2009, for a total study period of 76 months. Patients in this clinic were identied as having active coccidioidomycosis if they had one of the following conditions: (1) a positive coccidioidal serological test result, (2) a culture positive for Coccidioides species, (3) histopathological identication of coccidioidal spherules, or (4) clear documentation from an outside medical record of the diagnosis of coccidioidomycosis. All coccidioidal serological tests were performed by immunodiffusion using a commercially available kit (Coccidioides Immunodiffusion Systems; Meridian Bioscience) for tube precipitin and complement xation (IDCF) assays. Data abstracted from the medical records included the age, sex, race, and ethnicity of the patient. Results of the peripheral blood CD4 T lymphocyte cell count and percentage, the plasma HIV RNA level, coccidioidal serological tests, and chest radiographs were collected at entry and at follow-up visits. The

Table 2. Association between Type of Coccidioidal Disease and Parameters of Human Immunodeciency Type 1 (HIV-1) Infection and Treatment
Positive serological test result, nodule, or cavity 8 0 10 1 13 369 54

Parameter HIV RNA level, copies/mL

!50

Focal or diffuse alveolar disease 2 10 3 6 10 177 49

P
!.001

50 Potent ART Yes No CD4 T lymphocyte count, cells/mL No. of patients who had measurement Mean SEM

.007

.020

NOTE. ART, antiretroviral therapy; SEM, standard error of the mean.

2 CID 2010:50 (1 January) Masannat and Ampel

Table 3. Clinical Data at Diagnosis and during the Follow-Up Period for 6 Patients with Coccidioidomycosis Who Received No Antifungal Therapy
At diagnosis CD4 Type of Patient 5 7 8 15 17
a a

Duration CD4 HIV RNA level, copies/mL 125

!50 !50 !50

During follow-up CD4 T lymphocyte IDCF titer Neg Neg Neg Neg Neg Neg count, cells/mL 416 597 397 587 186 488 CD4 T cell lymphocyte percentage 25.2 34.3 23.4 29.5 14.7 21 HIV RNA level, copies/mL
!50 !50 !50 !50 !50 !50

of follow-up, months 19 29 56 62
176 176

T lymphocyte IDCF titer

!1:2

T cell lymphocyte percentage 19.5 33.0 22.0 17.0 5.0

presentation Nodule Positive serological test result Positive serological test result Positive serological test result Nodule Positive serological test result

count, cells/mL 300 578 383 508 56

1:8
!1:2

1:2 1:2
!1:2

27

NOTE. HIV, human immunodeciency virus; IDCF , complement xation; Neg, negative.
a

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Diagnosis was prior to entry to the clinic. At diagnosis data are from the time of entry to the clinic.

electronic pharmacy records were reviewed for whether the patient was receiving antifungal therapy and whether potent ART was prescribed. Potent ART was dened as the use of 3 antiretroviral medications in the context of no evidence of resistance to the drugs in HIV-1. The records of individuals with coccidioidomycosis who were either not treated with antifungal therapy or who had antifungal therapy discontinued were further reviewed through May 2009. For the case-control study, laboratory data collected for the control subjects were obtained at the rst clinic visit or, if the patient was already established in the clinic, at the time of initiation of the study. For the case patients, laboratory data obtained at the time of diagnosis of coccidioidomycosis were used. Statistical analysis included the Pearson x2 test for categorical variables and Students t test for analysis of continuous data. Continuous data are expressed as either the median and range or the mean standard error of the mean, as appropriate. This study was approved by the Human Subjects Protection Program of the University of Arizona and by the Research and Development Committee of Southern Arizona Veterans Affairs Health Care System. RESULTS Over the 64-month period of study, a total of 257 patients with HIV-1 infection attended the clinic. Of these, 29 (11.3%) had concomitant coccidioidomycosis and 12 (4.7%) received a diagnosis of coccidioidomycosis during the study period; the annual incidence of new cases of coccidioidomycosis was 0.9% (2.3 cases). Description of the cohort. Of the 29 patients with coccidioidomycosis, all but one was male, 27 were white, and the mean age was 47 years. At the time of diagnosis, the mean peripheral blood CD4 T lymphocyte count was 284 cells/mL (CD4 T lymphocyte percentage, 27%) among the 23 patients for whom it was available. Plasma HIV RNA level was available for 20 patients and was !50 copies/mL in 8 of these patients,

50400 copies/mL in 3, and 1400 copies/mL in 9. At the time of diagnosis, 13 patients were receiving potent ART, and 8 were not. It was not known whether the remaining 8 patients were receiving potent ART. The diagnosis was established by serological testing for 19 patients, culture for 5, and by histological testing for 1. For 4 patients, the diagnosis was based on review of the medical record from an outside facility. Fifteen of the 29 patients with coccidioidomycosis had chest radiographs showing a focal pulmonary process, of which 8 were alveolar inltrates, 5 were nodules, and 2 were cavities. Four patients had diffuse pulmonary disease, and 8 had positive coccidioidal serological test results without evidence of clinical disease. Only 2 patients had extrathoracic dissemination; both had received a diagnosis of meningitis before entering the clinic. No instances of immune response inammatory syndrome were observed. Twenty-one patients received antifungal therapy; 16 received uconazole, and 5 received itraconazole. Only 1 patient received a course of amphotericin B. Eight patients were not treated. At the end of the follow-up period, 2 patients had died. Neither death was attributable to coccidioidomycosis. Table 1 shows the clinical aspects of the 29 cases of coccidioidomycosis in the cohort, by type of coccidioidomycosis. There was a trend toward lower peripheral blood CD4 T lymphocyte count, higher HIV RNA levels, and a lower likelihood of having received potent ART with increasing severity of coccidioidal disease. When the less severe types of coccidioidomycosis (ie, presentation with positive serological test results, nodules, and cavities) were combined and compared with the more severe manifestations of disease (ie, presentation with focal and diffuse alveolar coccidioidomycosis), there were statistically signicant differences in the management and severity of HIV-1 infection between the 2 groups. As shown in Table 2, patients with less severe coccidioidomycosis were more likely to have an HIV
Coccidioidomycosis in the Potent ART Era CID 2010:50 (1 January) 3

Table 4. Clinical Data at Diagnosis and during Follow-Up for the 11 Patients with Coccidioidomycosis Who Initially Received Antifungal Therapy but for Whom It Was Subsequently Discontinued
At diagnosis At time of therapy discontinuation

Patient Neg 1:8

!50 !50

Type of presentation 379 260 18 3 72 30 12

176

CD4 CD4 T lymphocyte T cell lymphocyte IDCF titer count, cells/mL percentage Duration of therapy, months 6 13.8 8.7 24.0 10.0 11.0 16.0 18.0 10.0
1100,000 1100,000 !50

HIV RNA level, copies/mL

IDCF titer Neg Neg

!1:2

CD4 CD4 HIV T lymphocyte T cell lymphocyte RNA level, count, cells/mL percentage copies/mL 473 234 629 Neg
!1:2

1
!1:2

Nodule 503 193 71 227 526 505 61 67 716 12,100

14.5 7.0 23.0 116 181 Neg Neg 74 960 5.6 18.1 8.0 26.0

!50 !50

4 Neg 1:64 1:8 Neg 1:2 Neg

!1:2

Nodule

Nodule

7910
!50 !50 1100,000 !50

10

Focal pneumonia

11

Focal pneumonia

18

Positive serological test result

19

Focal pneumonia

21

Focal pneumonia

0.3 60 64 30

Neg Neg Neg Neg

526 584 386 408

16.0 36.0 24.0 25.0

67
!50

22

Positive serological test result

23

Positive serological test result

236 3720

26

Diffuse pneumonia

NOTE. HIV, human immunodeciency virus; IDCF , complement xation; Neg, negative.

Diagnosis was established prior to entry to the clinic.

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Table 5. Comparison of the 29 Patients with Coccidioidomycosis with the 228 Human Immunodeciency Virus Type 1 (HIV-1)Infected Control Subjects without Coccidioidomycosis Who Were Seen in the Clinic during the Same Period
Case patients Control subjects (n p 29) (n p 228)

Variable Sex Male Female Race White Black American Indian Other Unknown Ethnicity Non-Hispanic Hispanic Unknown Age, mean years SEM CD4 T lymphocyte count, mean cells/mL SEM HIV RNA level, mean log copies/mL SEM Potent ART No Yes

28 1 21 1 2 0 5 18 3 8 47.8 1.9 285 42 2.15 0.50 7 13

219 9 139 30 4 2 52 122 25 80 47.4 0.6 477 21 2.32 0.14 79 147

.923

.301

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.679 .837 .003 .735 .997

NOTE. ART, antiretroviral therapy; SEM, standard error of the mean.

RNA level !50 copies/mL, to be receiving potent ART, and to have higher peripheral blood CD4 T lymphocyte counts than were patients with more severe coccidioidomycosis. Six of the 29 patients did not receive antifungal treatment. At the time of diagnosis, 4 of these 6 patients had a positive serological test result only, and the other 2 had pulmonary nodules. The IDCF titer ranged from !1:2 to 1:8, and the median CD4 T lymphocyte count was 383 cells/mL (CD4 T lymphocyte percentage, 19.5%) in the 5 patients for whom data were available. The HIV RNA level was undetectable in 3 of the 4 patients for whom the measurement was obtained. The median duration of follow-up for these patients was 59 months (range, 19346 months). At the time of their nal follow-up visit, all had negative coccidioidal serological test results and no clinical evidence of active coccidioidomycosis. The median CD4 T lymphocyte count had increased to 452 cells/mL (CD4 T lymphocyte percentage, 24.3%), and all had undetectable HIV RNA levels (Table 3). An additional 11 patients received antifungal therapy that was subsequently discontinued. At the time of the diagnosis of coccidioidomycosis in these patients, 4 had focal pneumonia, 3 had pulmonary nodules, 3 had positive serological test results, and 1 had a diffuse pneumonia (Table 4). Their median CD4 T lymphocyte count was 408 cells/mL (CD4 T lymphocyte per-

centage, 18%). Plasma HIV RNA levels ranged from !50 copies/ mL to 1100,000 copies/mL, and the IDCF titer ranged from undetectable to 1:64. Antifungal therapy was given for a median duration of 30 months. The median CD4 T lymphocyte count at the time of discontinuation of antifungal therapy was 260 cells/mL (CD4 T lymphocyte percentage, 12%). The patients were subsequently followed up for a median duration of 50 months (range, 11111 months) after antifungal therapy was discontinued. At the time of the last follow-up visit, all 11 patients had either a negative or minimally detectable IDCF titer. The median CD4 T lymphocyte count was 450 cells/mL (CD4 T lymphocyte percentage, 19%), and none had evidence of active coccidioidomycosis (data not shown). Case-control study. Table 5 shows the comparison of the clinical aspects in the 29 case patients with coccidioidomycosis with those in the 228 patients with HIV-1 infection seen at the clinic during the same period who did not receive a diagnosis of coccidioidomycosis. There were no signicant differences between the 2 groups in sex, race, ethnicity, age, logarithmic measurement of the plasma HIV RNA level, or receipt of potent ART. However, patients who developed coccidioidomycosis had signicantly lower peripheral blood CD4 T lymphocyte counts than did patients who did not have the disease (P p .003).
Coccidioidomycosis in the Potent ART Era CID 2010:50 (1 January) 5

DISCUSSION These data reveal a marked decrease in the both the incidence and the severity of symptomatic coccidioidomycosis during the era of potent ART, compared with a study conducted prior to this era [12]. Although the original prospective study in this same clinic found an annual incidence of coccidioidomycosis of 7.3%, we found an annual incidence of only 0.9%, which is similar to the estimate of the incidence of symptomatic coccidioidomycosis in the general population [15]. Moreover, the clinical expression of coccidioidomycosis appeared to be less severe in our study than in the previous study. Of the 13 patients who developed active coccidioidomycosis in the prospectively observed cohort before the potent ART era, 5 had diffuse pulmonary disease, 4 had focal pulmonary disease, 2 had nodules, 1 had extrathoracic disseminated disease, and 1 had an isolated positive serological test result; 5 of these patients died. In the present study, which involved 29 patients, 15 had either nodules, cavities, or isolated positive serological test results; 8 had focal pulmonary infection; 4 had diffuse pneumonia; and none had documented extrathoracic disease. Moreover, only 2 died, and neither of these deaths was attributable to coccidioidomycosis. The only difference between the patients with coccidioidomycosis and the control subjects was a signicantly lower peripheral blood CD4 T lymphocyte count in the case patients. This is not surprising because a CD4 T lymphocyte count !250 cells/mL was associated with the development of coccidioidomycosis in the prospective study [12], and it has been subsequently found that this same concentration is associated with a loss of specic coccidioidal cellular immune responsiveness in patients with HIV-1 infection [16]. Although differences in CD4 T lymphocyte count between the case patients and control subjects may have been expected, it was revelatory that CD4 T lymphocyte count and overall treatment and control of HIV-1 infection were signicantly associated with the severity of the presentation of coccidioidomycosis. These results reveal the critical importance of appropriate potent ART for the prevention of opportunistic infections that occur during HIV-1 infection. Several patients did not receive any antifungal therapy for their coccidioidomycosis, and others had antifungal therapy discontinued during the follow-up period. There were no instances of recurrence in these groups, despite the relatively long follow-up period. These results are in keeping with results seen in non-immunocompromised patients, in whom pulmonary coccidioidomycosis generally improves without any specic therapy [17]. From these observations, we concluded that the improvement in immune function associated with use of potent ART has resulted in a decrease in the incidence and severity of coccidioidomycosis among patients with HIV-1 infection who live
6 CID 2010:50 (1 January) Masannat and Ampel

in areas where coccidioidomycosis is endemic, yielding an overall improvement in outcome. These results suggest that patients with CD4 T lymphocyte counts 1250 cells/mL who are receiving potent ART can be treated in much the same way as recommended for patients without HIV-1 infection [18], and they provide justication for the current US Public Health Service and Infectious Diseases Society of America Guidelines for the management of opportunistic infections during HIV-1 infection [11].
Acknowledgments
We thank Dr. John Galgiani for his advice during the preparation of this manuscript. Potential conicts of interest. F.Y.M. and N.M.A.: no conicts.

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