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Original Article

Coccidioidomycosis and Tuberculosis Coinfection at a Tuberculosis Hospital

Clinical Features and Literature Review

Cadena, Jose MD; Hartzler, Anthony MD; Hsue, Gunther MD; Longfield, Robert N. MD

Author Information
doi: 10.1097/MD.0b013e318194757a
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Abstract

INTRODUCTION

Tuberculosis (TB) is a common disease in many developing countries. In 2006, Texas had a TB rate of over 6.7 cases per 100,000 population (overall United States case rate, 4.6 per 100,000).5 A number of these cases are imported from neighboring Mexico, which has an even higher incidence of TB (up to 44.6 per 100,000 in the Mexican states immediately south of the Rio Grande).5,28 Primary pulmonary TB infection is usually associated with focal radiographic infiltrates and ipsilateral hilar lymphadenopathy. Reactivation of pulmonary TB often presents with nodules and cavitation, especially in the upper lobes.23

Coccidioidomycosis is an endemic mycosis of South America, northern Mexico, and the southwestern United States, including Texas. In 2005, 6542 cases of coccidioidomycosis were reported to the United States Centers for Disease Control and Prevention (CDC), but as many as 150,000 cases of self-limited infection occur every year.21,31 Patients with primary coccidioidomycosis may have a normal chest X-ray or focal infiltrates. Patients with chronic pulmonary coccidioidomycosis may develop cavities, hilar lymphadenopathy, and rarely, an intracavitary mycetoma. In patients with chronic progressive pulmonary coccidioidomycosis, the radiographic findings closely resemble pulmonary TB.7,40

Active TB disease and chronic pulmonary coccidioidomycosis share some common risk factors, including overlapping areas of endemicity (including south Texas) and increased occurrence among immunosuppressed patients. Furthermore, presenting syndromes may be similar, with protracted constitutional symptoms, respiratory symptoms, subacute meningitis, or reactivation of primary infection years to decades after initial exposure.11,23,31

While coinfection with TB and coccidioidomycosis has been described sporadically in the literature, most reports are over 30 years old.3,8-10,12,15,16,18,19,22,27,29,33-36,41 Recently reported cases were discovered incidentally in a coccidioidomycosis case series.26 Given similarities in the clinical presentation, the similar radiologic patterns of both infections, and the possible suppressive effect of TB therapy on the growth of Coccidioides immitis,13 diagnosis of coinfection can be challenging. Furthermore, the decrease in case rates of TB in the United States may have caused a reduction in the number of recognized coinfections, although the potential effect of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV-AIDS) on coinfection has not been examined.5,6

We conducted the current study to describe the clinical, epidemiologic, laboratory, and radiologic features of patients with coccidioidomycosis and TB coinfection, and their outcomes. We present here the cases of coccidioidomycosis and TB coinfection managed at an inpatient TB reference center over 12 years, and we describe, for the first time to our knowledge, a detailed case series of symptomatic patients from Texas, a case of coinfection with multidrug-resistant TB and coccidioidomycosis, and a patient with TB, coccidioidomycosis, and HIV-AIDS.

PATIENTS AND METHODS

We conducted the current study as a retrospective review from the Texas Center for Infectious Disease (TCID) in San Antonio, TX. TCID is a 71-bed referral hospital for persons requiring inpatient TB treatment. We identified patients by searching medical records for cases with International Classification of Diseases (ICD)-9 diagnostic codes of TB and coccidioidomycosis from January 1995 to December 2007. Patients were included if they were older than 18 years old and had a diagnosis of both TB (by culture) and coccidioidomycosis (by cultures or histology).

Data obtained included demographic characteristics; city of origin; comorbidities; use of alcohol, drugs, and tobacco; presenting symptoms; clinical course; laboratory findings; and response to therapy. Response to therapy was defined as microbiologic, radiologic, clinical, and (when available) serologic improvement at the end of follow-up. Laboratory studies evaluated include those at admission to the hospital and at the time of diagnosis of coccidioidomycosis infection (including blood cell counts, HIV serology, CD4 lymphocyte counts, and coccidioidomycosis serologies), and studies relevant to define the diagnosis of TB disease and results of mycobacterium susceptibility testing. Radiology reports and images were described before diagnosis of coinfection, if available; at the time coinfection was diagnosed; and at the end of follow-up. Therapy for TB and coccidioidomycosis was recorded until the end of follow-up.

Literature Review

We performed a PubMed (National Library of Medicine, Bethesda, MD) search with the terms "coccidioidomycosis" and "tuberculosis," including the cases where both infections were present in the same patient, concomitantly or sequentially. We defined the cases as those diagnosed by histopathologic or microbiologic methods. Other cases reported in English or Spanish were also included. Cases where the diagnosis of coccidioidomycosis was made solely by serology were excluded.

Statistical Analysis

Due to the retrospective nature of this series and the limited number of cases, statistical analysis included descriptive methods only. Continuous variables were reported as the mean ± standard deviation (SD) and categorical variables as percentages. This study was approved by the Institutional Review Board from the University of Texas Health Center at Tyler.

RESULTS

We identified 9 patients in the retrospective record review. Clinical and demographic characteristics of patients, symptoms, and therapy for TB and coccidioidomycosis are available in Table 1. Patients were usually male (8/9, 89%), Hispanic (7/9, 66%), and middle-aged (mean age, 42 ± 14 yr). Although most patients (6/9) were originally from Texas, 3 patients were born in Mexico. Three patients were tobacco smokers, 3 were heavy alcohol drinkers, and 1 reported cocaine use. Comorbidities varied among patients, and AIDS was present in only 1 case. Four patients had underlying lung disease at the time of diagnosis, including chronic obstructive pulmonary disease (COPD) in 3 cases and bronchiectasis in 2 cases. Two patients had diabetes mellitus.

TABLE 1
TABLE 1:
Characteristics of 9 Patients With TB and Coccidioidomycosis Coinfection

Risk factors for TB included AIDS (n = 1), incarceration (n = 2), homelessness (n = 2), and diabetes mellitus (n = 2). All patients had pulmonary TB, and 1 also had TB lymphadenitis. All patients were diagnosed with coccidioidomycosis after being diagnosed with TB; all patients were diagnosed by sputum fungal cultures and coccidioidomycosis serologies, which are routinely performed on all patients admitted to TCID. However, only 3 cases (33%) had positive fungal sputum smears. Two cases had evidence of new coccidioidomycosis infection during hospitalization, with initially negative serology and sputum fungal culture on admission. One case (Case 4) remained highly symptomatic despite treatment for TB and was therefore retested and found to have positive coccidioidomycosis serology and sputum culture 6 months after admission. He was ultimately diagnosed with COPD and bronchiectasis. The second case (Case 9) was under treatment for multidrug-resistant TB and developed new symptoms 2 years, 8 months after admission. She was found to have an air-fluid level inside a previously noted pulmonary cavity. Serologies and fungal cultures, initially negative on admission, were positive for Coccidioides species at the time the new symptoms developed. All patients had pulmonary coccidioidomycosis except 1 patient who had disseminated disease including coccidioidal meningitis (Case 1) in the setting of AIDS.

Laboratory findings are shown in Table 1. Anemia was common (present in 5 cases; mean hemoglobin, 11.9 ± 2.3 g/dL; reference value: 12-16 g/dL) but leukocytes were only mildly elevated (3 cases). All patients were screened with enzyme-linked immunosorbent assay (ELISA) for HIV 1-2, but only 1 tested positive and was proved to have AIDS with a CD4 lymphocyte count of 20 cells/mm3. Four patients (45%) had negative sputum cultures for TB at the time of coccidioidomycosis diagnosis but all had positive sputum cultures for Coccidioides species.

Therapy included TB medications and an antifungal triazole in most cases. Three patients were managed with itraconazole. One of these was switched to fluconazole because he developed anterior uveitis on rifabutin and was switched to rifampin (Case 2). Four patients received fluconazole, and 2 patients received no specific treatment for coccidioidomycosis. Two patients died: 1 with AIDS and disseminated coccidioidomycosis (Case 1), and another who developed a new infiltrate and subsequent respiratory failure (Case 5).

Radiologic findings were similar to those of patients with pulmonary TB (see Table 1). In the cases with prior radiographs available, only 1 showed changes associated with the onset of symptoms: an air-fluid level appeared in a preexisting lung cavity (Case 9; Figure 1, A and B). The patient had already completed the therapy for multidrug-resistant TB. In this instance, the findings resolved following 12 months of treatment with itraconazole.

FIGURE 1
FIGURE 1:
Patient 9: Computer tomography of the chest. A, Left lower lobe cavitary lesions, presumably secondary to active TB. B, Development of air-fluid levels at the time of coccidioidomycosis diagnosis. Patient had already completed TB therapy.

DISCUSSION

Coccidioidomycosis and TB are not frequently reported to cause coinfection. Over the previous 25 years, reports of TB and coccidioidomycosis coinfection have been uncommon. Papers published in the 1940s to 1960s described coinfection with greater regularity; however, the clinical presentations were diverse.3,8-10,12,15,16,18,19,22,27,29,33-36,41 Published case reports included coccidioidal cavities thought to be secondarily infected by TB, and vice versa.10

All symptomatic patients reported had lived or worked in coccidioidomycosis-endemic areas. Most patients were reported or had lived in Arizona or California.3,8-10,12,15,18,19,22,27,29,33-36

In the present case series, TB and coccidioidomycosis coinfection was difficult to distinguish clinically and radiologically from TB or coccidioidomycosis monoinfection.23,31 A few patients had persistent or relapsing symptoms despite receiving appropriate therapy for TB, and were subsequently found to have coccidioidomycosis coinfection.

Epidemiology and Demographic Characteristics

In our search of the literature, we identified 66 cases of proposed TB and coccidioidomycosis coinfection.3,8-10,12,15,16,18,19,22,27,29,33-36,41 Of those, 35 fulfilled our inclusion criteria for further review.3,8-10,12,15,16,18,19,27,29,33-36 Clinical characteristics of the cases are listed in Table 2.

TABLE 2
TABLE 2:
Characteristics of Patients With TB and Coccidioidomycosis Coinfection, Previous Reports

Patients were predominantly male (25/35, 71%). The most common ethnic group was white (21/35, 60%), followed by Hispanic (6/35, 17%) and African American (4/35, 11%). Ages ranged from 3 to 62 years (median, 40 ± 15 yr).

The median age of reported patients is similar to that found in our patients, although we had more Hispanic patients, with most cases residing in south Texas or recently immigrated from Mexico. The real incidence of coccidioidomycosis in Mexico is unknown, but skin test-based epidemiologic surveys suggest that coccidioidomycosis prevalence varies between 10% and 93% in the northern states of Mexico that border the United States.20 There is certainly a high incidence of TB in the area along the United States-Mexican border, which also corresponds to the coccidioidomycosis-endemic region.26,28 Finally, although the risk of acquiring coccidioidomycosis seems to be the same among different races, some authors have suggested that Hispanic patients may be at higher risk for progressive or extrapulmonary coccidioidomycosis than white patients.11,17

Coccidioidomycosis and TB are diseases that are not often reported concomitantly. This by no means indicates a lack of association between the diseases. Although there are no prospective studies on the subject, 1 study that aimed at reporting coccidioidomycosis over a 9-year period in a predominantly Hispanic population in south Texas, found that of 41 patients with coccidioidomycosis, almost 10% also had concomitant pulmonary TB.26 The occurrence of the coinfection has multiple common epidemiologic links, including overlapping endemic regions and similar immunologic responses required to protect the host from active disease by both pathogens.23,31,38 Both diseases occur with increased incidence in patients receiving immunomodulatory therapies, including corticosteroids and, more recently, TNF-α antagonists.38

Clinical and Laboratory Features

Cotton et al10 made an attempt to classify the coinfection based on its possible pathogenesis. However, this is difficult given the similarity in the clinical presentation of coccidioidomycosis and TB and the wide variability of clinical details provided in published reports. Nevertheless, based on case reports and authors' comments in the 35 reports in our literature review, we identified 9 cases (25.7%) in which coccidioidomycosis preceded TB, and 9 cases (25.7%) in which TB preceded coccidioidomycosis. We found 16 cases (45.7%) where the infections were diagnosed simultaneously, and 1 case (2.9%) where the infection occurred at different times in different areas of the lung (coincidental).3,8-10,12,15,16,18,19,27,29,33-36

Among 21 patients in the literature who had a description of the clinical features during the course of the infection, the most prevalent features were respiratory symptoms (frequently including cough and hemoptysis), chest pain (usually pleuritic), and constitutional symptoms (weakness, weight loss, and night sweats). Fever was reported in fewer than half.3,8,9,12,16,18,19,27,29,33-36

In our series, 6 patients had fever and most had respiratory symptoms (8/9). Hemoptysis was common (4/9), as well as weight loss (6/9) and anorexia (3/9).

Patients in previously reported series had fewer comorbid conditions than patients in the current study. In the previous reports we found only 4 cases (4/35, 11%) of diabetes mellitus, 1 case of immunosuppression in the setting of renal transplantation, 1 case of coinfection with an immunosuppressing pathogen (measles), 2 cases (2/35, 6%) of alcoholism, and 1 case of heroin use.3,8,9,12,16,27,33,35 In our series, diabetes mellitus was diagnosed in 2/9 patients (22%), structural lung disease in 4/9 patients (44%), and alcoholism in 3/9 patients (33%).

In the cases of TB and coccidioidomycosis reported in the literature, the lungs were the most commonly compromised organs, usually with associated cavitation.3,8-10,12,15,16,18,19,27,29,33-36 Seven of the 35 patients (20%) developed disseminated or extrapulmonary coccidioidomycosis, and 4 patients (11%) developed disseminated or extrapulmonary TB.3,8,9,15,18 It is interesting to note that all patients with disseminated or extrapulmonary TB also had disseminated or extrapulmonary coccidioidomycosis.8,15,16,18 There was predilection of coccidioidomycosis for bone and soft tissue (calcaneus, phalanx, humerus, femur, skull, and soft tissue adjacent to areas of bony involvement) and skin, and 3 patients had disseminated disease to multiple organs.3,15,18

To our knowledge, there are no previously reported cases in the literature of TB and coccidioidomycosis coinfection in the setting of HIV infection. The CDC considers disseminated or extrapulmonary coccidioidomycosis an AIDS-defining condition, while both pulmonary and extrapulmonary TB qualify.4 In the current series, the patient with AIDS, pulmonary TB, and TB lymphadenitis developed fatal disseminated coccidioidomycosis, including pulmonary and meningeal involvement despite therapy with appropriate TB agents, antiretroviral therapy (nelfinavir, zidovudine, and lamivudine), and high-dose fluconazole.

An important number of patients with HIV living in endemic regions may be at risk for progressive pulmonary or disseminated coccidioidomycosis. The CD4 count at the time of coccidioidomycosis disease in HIV patients1 is usually <250 cells/mm3. On the other hand, TB can occur at any CD4 count, and it can accelerate the decline in CD4 cells in patients with HIV. Due to the low and declining incidence of TB in the United States, HIV TB is more commonly reported in HIV-positive persons with very low CD4 lymphocyte counts.5,23 The reason for the lack of reports of coccidioidomycosis and TB coinfection in the setting of AIDS is not clear.1

Coccidioidomycosis was consistently diagnosed by sputum cultures. Of 17 patients with complement fixation results reported, 8 (47%) were positive on initial testing, 5 (24%) were initially negative but became positive, and 2 (12%) remained negative. In the remaining 2 cases, the authors did not record the date or time of initial testing.8,9,10,19,29,34,35

Serologic testing was commonly reported in older series, and complement fixation may be helpful in the diagnosis and follow-up of patients with coccidioidomycosis. However, given multiple testing protocols, it is difficult to compare titers obtained at different centers. Furthermore, the sensitivity of complement fixation alone may be as low as 56%, particularly among immunosuppressed patients.30

Nineteen patients had purified protein derivative (PPD) testing done. Of these, 15 patients (79%) were reported positive. However, PPD testing materials and methods were not consistently documented.8,9,15,18,19,27,29,33-36

In our series we observed that the coinfection was more common among patients who failed to improve despite effective antitubercular therapy. It is interesting to note that clinically, the 2 diseases may be indistinguishable, and it may be prudent to always consider the coinfection among patients coming from coccidioidomycosis-endemic regions. There are some clinical features that may suggest the presence of the coinfection, but all patients from endemic regions should be considered at risk (Table 3).

TABLE 3
TABLE 3:
History, Clinical, and Laboratory Clues Suggesting Coinfection With Coccidioidomycosis in Patients With TB

Radiologic Features

Patients presenting with pulmonary coccidioidomycosis or TB monoinfection may have similar radiologic features. TB disease can often be divided into primary disease (focal infiltrates, often in the lower lobes, occasionally associated with ipsilateral hilar or paratracheal lymphadenopathy and less commonly, miliary infiltrates) or postprimary disease (dense infiltrates in the apical, posterior segments of the upper lobes and cavities with thick, irregular walls).2

Primary coccidioidomycosis presents as a unilateral, mass-like consolidation, associated with lymphadenopathy in about 20% of cases. Some cases evolve into chronic progressive coccidioidomycosis, characterized by bilateral infiltrates, nodular with cavitation, and others into a nodule or a mass-like coccidioidoma. Some other patients develop upper lobe thin-walled cavities of variable size.32 Rarely, patients develop disseminated disease with a miliary distribution and mediastinal lymphadenopathy.2

Radiologic features reported in the literature in the setting of TB and coccidioidomycosis coinfection were diverse (see Table 2). They varied depending on the age of the patient and the stage of the disease (with the tendency to develop cavitation as the disease evolved, commonly encountered in TB monoinfection). Most patients eventually developed cavitary disease, most commonly involving the upper lobes. In other patients, especially those with disseminated disease, a miliary pattern was noted.

Therapeutic Implications and Clinical Outcomes

Previous series in the literature were limited by the small number of patients and by the lack of safe and effective therapy. In the pre-antibiotic era, many patients with pulmonary TB would experience disease remissions and exacerbations, occasionally helped by supportive care under the sanatorium model. Many cases of coccidioidomycosis would have been self limited and eventually resolve without specific therapy. In the current series, we observed a favorable response to concomitant TB and coccidioidomycosis therapy in our 9 patients, except for the fatal outcome of disseminated coccidioidomycosis in the setting of AIDS. As with our patient who received less than 2 weeks of triazole therapy before death, patients who complete at least 2 months of antifungal therapy have the best outcomes.

Medical therapy of coccidioidomycosis can be complicated by the drug interactions between triazole antifungal agents and TB medications. Rifampin induces CYP450 (CYP3A4) in the liver and intestine, which may decrease the area under the curve (AUC) of itraconazole by 80%-90% and the AUC of fluconazole by 23%.24 The concomitant use of itraconazole and rifampin is not recommended. Patients treated with fluconazole for severe coccidioidomycosis (such as meningitis) may have better outcomes when higher doses are used, and rifampin should, again, be used with caution in this setting.24,39

Diagnostic and pharmacologic advances for the diagnosis and treatment of coccidioidomycosis and TB make it easier to both diagnose and treat coinfection. The clinician should consider both diseases in the differential diagnosis of a patient with these demographic and geographic risk factors.23,31 It is not clear whether all coinfected patients need antifungal therapy in addition to their TB regimen. Many Coccidioides immitis infections are self limited, and most previously reported cases were described before current triazole antifungal agents became available.8-10,12,15,18,19,22,27,29,33-36 However, there may be certain clinical settings in which concurrent TB and antifungal therapy is warranted.3,8,17

The current case series has limited applicability to clinical practice. First, this was a retrospective study and the data were obtained at a TB referral hospital. Second, due to limited patient numbers, we cannot comment on whether coinfection adversely affected patient outcomes. In addition, it is likely that some patients may develop undetected and self-limited pulmonary coccidioidomycosis during management for active TB.14,37

In conclusion, TB and coccidioidomycosis can coexist in the same host, as they share geographic endemicity as well as significant predisposing conditions (such as HIV infection). The rare but significant co-occurrence of TB and coccidioidomycosis illustrates the need to obtain a detailed epidemiologic history for patients diagnosed with TB. TB with coccidioidomycosis coinfection is often indistinguishable from TB alone, but can manifest as relapsing pulmonary or extrapulmonary symptoms in the setting of seemingly adequate therapy for TB. Both diseases may have a fulminant course in immunosuppressed individuals. Patients in endemic areas should be evaluated for the potential of coinfection and treated when clinically indicated.

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