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Coccidioidomycosis: A Regional Disease of National Importance: Rethinking Approaches for Control
- John N. Galgiani, MD
Abstract
Coccidioidomycosis is an increasingly important health problem because of the migration of large numbers of persons to portions of the southwestern United States in which the disease is endemic and because of the increasing numbers of immunosuppressed patients. Most infections due to Coccidioides immitis, although causing significant illness, are self-limited and resolve over a period of weeks to months without specific treatment. It is not known whether antifungal treatment of early infections hastens resolution of the primary illness or prevents complications. Even so, diagnosis of early infections is of value for allaying patient anxiety, lessening the need for further diagnostic studies, decreasing empirical use of antibacterial agents, and facilitating early identification of patients with complications that are more serious. Patients who develop chronic coccidioidal pneumonia or extrapulmonary infection often have complicated courses that require the involvement of various medical, surgical, and radiologic subspecialties for management. Improvement of the ability to control the problem of coccidioidomycosis will require research into the molecular and cellular biology of C. immitis, vaccine development to prevent coccidioidal infection, a better understanding of the soil ecology that supports the fungus in its endemic regions, and discovery of new antifungal drugs. In addition, government agencies, colleges, the military, and employers could improve public health by initiating education programs about the most common manifestations of the disease among persons at risk for infection.
In describing the first two North American patients with “coccidioidal granuloma” more than a century ago, a Stanford surgeon speculated, on the basis of the patients' travel histories, that their infections were contracted in the San Joaquin Valley of California (1, 2). Six years later, the true cause was determined to be a fungus, Coccidioides immitis(3); however, it was not until 1936 that the rare and morbid systemic disease of coccidioidomycosis was linked to the self-limited regional disease known as San Joaquin fever (4). In 1957, Edwards and Palmer published a classic demographic study in which dermal delayed-type hypersensitivity to coccidioidin was measured in 48 676 young adults from across the United States who had lived their entire lives in the county in which they were born (5, 6). The findings from that study pinpointed the highest prevalence of infection as the rural south-central valley of California and the low deserts of southern Arizona. Concurrent work by Smith and colleagues, especially in correlating clinical manifestations of disease with newly developed serologic tests for coccidioidomycosis, produced a detailed picture of the spectrum of illness (7-11). Despite this research, coccidioidomycosis has been rediscovered as an “emerging disease” nearly a half-century later (12, 13). Why a well-understood disease should be considered new is primarily rooted in demographic trends that by most projections should continue to raise the importance of coccidioidomycosis both to the southwestern United States and the nation as a whole.
Perhaps the most important trend has been the massive migration of Americans to the Sunbelt states and, in particular, to Arizona, which in 1996 was the third-fastest-growing state in the United States. The Table shows population trends in several representative cities from the middle of the 20th century and into the next. The regions in Arizona in which C. immitis is most intensely endemic were previously sparsely populated and now contain major population centers, filled primarily with persons who have moved from areas where C. immitis was not endemic. Similar expansion has also occurred in central California and west Texas.
As these endemic populations have expanded, a growing segment of persons unusually susceptible to the most serious consequences of infection has also emerged. Corticosteroid therapy, antineoplastic chemotherapy, immune suppression for organ transplantation, and diseases that impair cellular immunity profoundly increase the susceptibility to life-threatening coccidioidal infections (14, 15). Because of the increasing application of organ transplantation (16-18) and the spread of the AIDS epidemic (19-22), coccidioidomycosis has become a common opportunistic infection. Although this problem is still most apparent in the endemic parts of the United States, it is by no means limited to these areas because suppression of cellular immunity permits reactivation of infections acquired years earlier (15, 18, 23, 24). For example, 46% of reported coccidioidal infections in patients with AIDS were identified in persons outside of the endemic regions (19). The mobility of modern society makes what was once a disease of regional importance now one that must be considered relevant throughout the country.
Less well understood are the effects on risk for infection brought about by changes in the fungus itself or in its ecologic environment. Variability among strains of the fungus has been recognized for some time, and recent molecular approaches have provided further evidence of this diversity (25, 26). Seasonal variations in infection rates and some outbreaks of coccidioidomycosis can be partially related to rain patterns, dust storms, or earthquakes (27-30). However, none of these factors have been implicated in the multiyear epidemic that occurred in the central valley of California during the first part of the 1990s; at its peak in 1992, this epidemic produced nearly 15 times as many reported cases as in nonendemic years (31-33).
The recognition of coccidioidomycosis as a health problem of emerging importance provides an opportunity to reassess the management of this disease, not only in individual patients but also in terms of institutional and public health policy. Approaches that seemed useful to manage a problem affecting small rural populations may now need to be revised for a risk that affects many millions of persons. This review is intended to raise for consideration possible actions that, if instituted, could promote public health at many levels. By raising these issues now, a consensus may be achieved that would help reduce the effect of coccidioidomycosis on the expanding population at risk.
The Primary Care Setting
The Importance of Early Diagnosis of Coccidioidomycosis
In the past, the value of diagnosing initial coccidioidal infections was not given much attention. One reason is that most coccidioidal infections are self-limited. Only 5% to 10% of infections result in any residual sequelae, many of which have few long-term effects (34). This has led many primary care providers, especially those in the endemic areas, to discount the need for early diagnosis of coccidioidal infections, even when symptoms lead patients to seek medical attention. In addition, serologic testing incurs a cost. For example, at the University of Arizona Student Health Service in Tucson, where clinic physicians have been particularly interested in attempting to establish a serologic diagnosis of symptomatic early coccidioidal infections (35-37), approximately six times more patients are tested for anticoccidioidal antibodies than are found to be serologically reactive. Because serologic testing costs approximately $40 per assay, testing at that facility costs nearly $250 per diagnosed infection. To some, this seems like an unnecessary expense and dissuades them from pursuing a diagnosis for what is often a self-limited process.
On the other hand, there are persuasive reasons why identifying coccidioidal infections will improve patient care, even when specific therapy is not necessary for initial management. First, coccidioidal pneumonia is frequently a debilitating infection associated with unsettling signs and symptoms, including protracted fever, fatigue, and weight loss. In college students, for example, time lost from class as a result of coccidioidomycosis was similar to that lost because of mononucleosis (35). Identifying a specific cause for these symptoms is often valuable both for reducing fears of other diagnoses, such as cancer, and for informing the patient about the likely course of the illness. Second, establishing a specific diagnosis obviates the need for further diagnostic evaluations that may be expensive or pose some risk. Third, a specific diagnosis of coccidioidomycosis removes the need to treat the patient empirically for the possibility of another type of infection. Fourth, and perhaps most important, identifying coccidioidal infections when they first occur facilitates earlier recognition of complications. Although uncommon, complications can be serious. Progressive coccidioidal infections usually emerge in the first months after the initial exposure (38). Therefore, a subacute or seemingly minor new symptom, such as back pain or headache, in the context of a recent case of coccidioidal pneumonia may signal spread of infection outside of the lungs; a full evaluation may be appropriate. Earlier identification of patients with progressive infections will permit earlier institution of antifungal therapy, less destruction of tissue or bone, and an overall reduction in the morbidity attributable to the disease.
Specific Tests for Diagnosing Coccidioidal Infections
For patients outside of the endemic regions, prompt diagnosis of coccidioidal infection depends on obtaining an accurate travel history. It is impossible to emphasize this point too strongly. If travelers to endemic regions were effectively informed of the possibility of coccidioidal infection from their travels, they themselves might raise this possibility with their physicians if they develop symptoms of infection (39, 40). Otherwise, only physicians who remember to obtain a recent travel history will be likely to consider the possibility of coccidioidal infection so that the appropriate tests are ordered. For patients with immunosuppressive conditions or therapies, such as AIDS, solid-organ transplantation, or lymphoma, it is important to be aware of even distant exposure to endemic regions because late recrudescence of latent infection is possible in such patients (23).
Because the signs, symptoms, and routine laboratory studies for patients with primary coccidioidal infections are relatively nonspecific (36), the diagnosis of coccidioidomycosis is almost always based on specific laboratory testing. A diagnosis is definitively established by seeing spherules in tissue or growing C. immitis in fungal cultures. Spherules do not take up Gram stain but may be visualized with potassium hydroxide, calcofluor, or Papanicolaou preparations of respiratory secretions (41, 42). Culture results are more sensitive than direct examination of clinical material, with growth usually occurring within the first week of incubation (43). Final identification of a mold as C. immitis requires further testing. In the past, several weeks were needed to demonstrate spherules either by animal inoculation or in vitro methods (44) or to prepare extracts from the fungus for reaction with specific antibodies (45). More recently, a commercially available DNA probe has reduced the time needed for confirmatory testing to a matter of hours (46).
Although cultures are often used to diagnose coccidioidomycosis in patients with disseminated infection, they are often not obtained in patients with primary infections; instead, diagnosis most frequently relies on serologic testing. Reference mycology laboratories have provided highly specific serologic testing for more than 40 years (47). For smaller laboratories, equivalent specificity can be obtained from commercial kits based on double immunodiffusion techniques or enzyme-linked immunosorbent assays (48-50). Although serologic tests for coccidioidomycosis are highly specific when the results are positive, they may yield false-negative results, especially early in the course of illness (37). Repeated serologic testing during the first 2 months of illness increases the possibility of establishing a diagnosis.
Management of Newly Diagnosed Coccidioidal Infections
Once a coccidioidal infection is diagnosed in the primary care setting, subsequent management depends on 1) other conditions that might modify the patient's risk for complications, 2) findings from a careful review of systems and physical examination, and 3) the course of the infection with further follow-up. Associated conditions that are particularly important risk factors include immunosuppressive diseases or therapies (14-17, 20, 21, 51-56), pregnancy in the late stages (57, 58), and diabetes (27). Persons of African or Philippine descent may also have an increased risk for extrapulmonary complications (59). To detect the presence of extrapulmonary infection, careful review of symptoms and physical examination is usually adequate because coccidioidal lesions are typically focal and produce localized symptoms, such as discomfort, swelling, or ulceration. Evidence of such focal abnormalities that have developed since the onset of the primary infection should be regarded with a higher degree of suspicion than might otherwise be warranted. For example, biopsy should be done on chronic or subacute nonhealing ulcers, joint effusions should be aspirated, persistent headaches may prompt a lumbar puncture, and skeletal symptoms might prompt bone scans or other imaging procedures to screen for osteomyelitis (60-62).
Most patients who have neither associated risk factors for complications nor specific evidence of progressive infection according to history or physical examination may be managed without antifungal therapy. The physician keeps in contact with these patients through periodic visits until the illness resolves. During the first several weeks of illness, systemic signs of weight loss, persistent fever, and progressive fatigue should resolve or markedly diminish. Their persistence would be cause for concern and should prompt reconsideration of the need for therapy. Serial serologic testing for complement fixing-type anticoccidioidal antibodies is also of value because increasing antibody titers are associated with progressive disease (47). Occasional chest radiographs are helpful for detecting pulmonary progression not present initially. The desirable interval between repeated visits, serologic tests, and chest radiographs ranges from 1 week to several months, as seems most appropriate to the clinician. In general, intervals are shorter early in the course of the illness and longer as the illness resolves.
The value of antifungal therapy in patients with mild or moderate manifestations of early infections is not known because randomized comparisons between antifungal and placebo regimens have not yet been done. In the absence of such studies, it is difficult to recommend treatment to all patients with newly diagnosed coccidioidomycosis. On the other hand, treatment may hasten symptom resolution. Thus, on a case-by-case basis, physicians should decide whether a patient's circumstances warrant therapy with available oral antifungal agents such as ketoconazole, itraconazole, or fluconazole. Although opinion on the most relevant factors with which to judge severity varies, commonly used indicators are loss of body weight greater than 10%, intense night sweats persisting longer than 3 weeks, infiltrates involving more than half of one lung or portions of both lungs, prominent or persistent hilar adenopathy, anticoccidioidal complement-fixing antibody titers in excess of 1:16, failure to develop dermal hypersensitivity to coccidioidal antigens, inability to work, or symptoms that persist more than 2 months. If treatment is initiated, reasonable dosages are 400 mg/d for ketoconazole, 400 mg/d for fluconazole, and 200 mg twice daily for itraconazole. Courses of typically recommended treatment would range from 3 to 6 months.
Use of Specialists in a Multidisciplinary Approach
The needs of the minority of patients with either high risk for or actual evidence of progressive coccidioidal infection vary widely and often are very complicated. The need for specific antifungal therapy, the selection of the most appropriate agents, and the use of these agents are often highly individualized decisions that are not easily described by flow diagrams or algorithms. Treatment options include amphotericin B and oral azole antifungal agents (ketoconazole, itraconazole, and fluconazole). Responses may require therapy to be continued for many months, even for life, to prevent relapses (63-74). For such patients, consultation with a variety of specialists is often beneficial. Depending on the source of increased risk or the organs involved in complications, management of specific infections may be enhanced by advice from specialists in pulmonary medicine, infectious diseases, neurology, orthopedic surgery, neurosurgery, and thoracic surgery. A multidisciplinary approach is especially important for coccidioidal meningitis or infections involving the spinal column. In these patients, neuroradiology may be especially useful (75). For example, abscesses within and adjacent to thoracic vertebrae may first require detailed magnetic resonance imaging and analysis by a neuroradiologist to assess the risk to the spinal cord; the next step may be surgical drainage by a neurosurgeon or orthopedic surgeon in cooperation with a thoracic surgeon. In patients with numerous extrapulmonary lesions involving multiple organs, a team approach is critical. A more detailed discussion of current therapy for the more complicated aspects of coccidioidomycosis may be found elsewhere (34, 76-78).
Opportunities for Research
The preceding section emphasizes ways in which current knowledge and resources might be better used to manage patients with coccidioidomycosis. Even if these measures are optimized, however, the initial effect of this disease on patients and treatment failure in some patients would continue to make coccidioidomycosis a serious problem. Thus, continued research into the biology, immunology, and treatment of C. immitis is needed to create new opportunities for prevention or control. The following discussion touches on several of the ways in which new studies could be conducted, and many other approaches would doubtless be possible or perhaps even more productive.
Fungal Pathogenesis and Genetics
Coccidioides immitis is one of a few fungi that can survive the transition from a saprobic to an invasive existence. However, we know almost nothing about the specific characteristics responsible for this capacity. Through recent developments in DNA technology, it is now possible to study such questions directly in fungal pathogens at the molecular level. For example, specific genes that affect virulence have been disrupted or replaced in Cryptococcus neoformans(79-85). Moreover, the techniques needed to perform such studies with C. immitis have already been applied to similar organisms such as Histoplasma capsulatum and Blastomyces dermatitidis(86-89). Taking the same approach in studies with C. immitis is clearly feasible and would significantly increase our understanding of how this fungus produces disease.
Immunologic Control and Vaccine Development
That so many patients can heal by developing immunity after coccidioidal infection has been appreciated for decades. Although studies of experimental infections of mice implicate cellular immunity as a crucial element in control (90-96), the programming and regulation of a competent immune response have only begun to be defined (97, 98). Even less is known about normal regulation of human cellular responses to C. immitis(99) and how these responses differ in patients with uncontrolled infection.
Another area that needs further research is the definition of which C. immitis antigens stimulate protective immunity. Although mice vaccinated with formalin-killed whole spherules are protected from otherwise fatal intranasal infection (100-105), only relatively small doses of this vaccine are tolerated by humans; in addition, these doses were insufficient to produce protection (106). It may be possible to identify subcellular fractions of the whole spherule that retain immunogenicity but are better tolerated (107). Another approach has been to clone genes that encode specific proteins and to overexpress them as recombinant proteins to prepare vaccines that are even more specific. Recent experimental evidence regarding this approach has been encouraging (108, 109). Cloned genes that encode antigens can also be used directly as a DNA vaccine that results in immunization by protein expression in situ (110). All of these strategies, which are just beginning to be pursued, offer hope for a practical vaccine to prevent coccidioidal infections altogether.
Ecology of Coccidioides immitis in Its Endemic Environment
Coccidioidomycosis is endemic to some regions and not to others. Even when dust storms or fomites distribute coccidioidal arthroconidia to nonendemic regions, the fungus typically does not extend its geographic range. Although the endemic regions have well-known general ecologic characteristics, little is known about the specific ecologic niche required for C. immitis to flourish.
In the 1950s and 1960s, attempts were made to understand the factors responsible for coccidioidal endemicity in the organism's desert habitat (111-117). Because the number of nonpathogenic strains of fungi in soil is so great, C. immitis was isolated by inoculating soil samples into mice. This procedure was tedious and resulted in slow progress. Recently, scientists interested in the ecology of other soil microbes have begun to use molecular tools, such as polymerase chain reaction, to detect the presence of specific organisms more efficiently. Because species-specific DNA sequences are known for C. immitis(118-120), this approach might also work to prepare accurate maps for locations of intense coccidioidal growth. The ability to define soils containing C. immitis would be valuable for identifying other associated ecologic factors with a precision not previously possible. This, in turn, could lead to experiments in modifying the soil, possibly resulting in diminished support of the fungus within the terrain. The ability to detect C. immitis in the soil may also be useful for assessing the risk to persons planning to disrupt it, such as might occur by housing construction, mining, or farming.
Antifungal Drug Development
Not all patients who need antifungal therapy respond to treatment. Moreover, in many of those who do respond, active infection recurs if antifungal therapy is stopped. This is most striking for patients with meningitis who discontinue oral azole therapy; in one report, 14 of 18 such patients had relapse (64). These limitations of current therapies for coccidioidomycosis underscore the need for new and more effective agents. After the discovery of amphotericin B in the 1950s, only one new antifungal drug (flucytosine) emerged in the next two decades. Since then, miconazole and subsequently three other commercially available agents of the same class (ketoconazole, fluconazole, and itraconazole) have shown therapeutic value for treating systemic fungal infections. The slow pace of drug development during this period was due, at least in part, to the perception that demand for these agents was lacking. Recent statistics, however, would seem to dispute that assumption. For example, 1995 world sales for fluconazole, itraconazole, and ketoconazole have been reported to be $879 million, $445 million, and $335 million, respectively (121). These observations have encouraged several pharmaceutical firms to increase their programs for development of antifungal drugs, resulting in an acceleration of clinical trials with new compounds.
Several avenues of investigation seem promising. The success of azole antifungal agents has led to the development of several additional congeners, some of which are now in clinical trials and may have use in treatment of coccidioidomycosis (122, 123). Lipid formulations of amphotericin B may improve the safety of this well-established agent (124, 125). However, studies are not currently available in patients with coccidioidomycosis to assess this attractive possibility. In addition, two new classes of compounds, the nikkomycins and the echinocandins, have emerged as cell-wall-inhibiting agents. Nikkomycin Z is an inhibitor of the enzyme chitin synthase. Coccidioides immitis is particularly susceptible to this agent, and there is hope that it may be developed for clinical use in the near future (126). Echinocandins demonstrate activity against the mycelial phase but, as yet, not against the spherule phase of C. immitis(127). Further modifications of this family of agents may improve its activity to the point of practical importance.
Although coccidioidomycosis represents a minor fraction of the present demand for antifungal drugs, patients with this disease are in as much need of help as those infected with more common mycoses. As pharmaceutical firms set the discovery of new agents for treating systemic mycoses as a long-term goal, coccidioidomycosis should be included in their drug development plans.
Reassessment of Institutional Policy
In Arizona, California, and Texas, increasing numbers of residents are affected by coccidioidomycosis. As a result, employers in these areas increasingly face lost days from work and substantial medical costs attributable to coccidioidal disease. Such organizations as the military, schools, travel agencies, and employers with national applicant pools actually create the opportunity for groups to relocate to or visit endemic regions, with subsequent risk for exposure. For these institutions, the issue is further complicated by the possible liability for the occurrence of infections that would otherwise not have happened. Although the risk for complications incurred by each person is slight, that risk is multiplied by the number of persons attracted to the Southwest. Consequently, among large groups of persons, it is almost certain that some persons will become seriously ill. This pattern of risk has been highlighted in recent reports (39, 40).
It is not clear to what extent an institution is legally responsible for coccidioidal infections in its constituents. Although the likelihood that institutions might be held responsible for such infection seems remote, some law suits have been settled otherwise (128, 129). On the other hand, a proactive risk management strategy might reduce the potential for institutional liability as well as have a salutary effect on public health.
Because coccidioidomycosis cannot yet be prevented within endemic regions, the single most important activity that affected institutions could undertake today would be to develop educational programs for their employees, students, or other constituents. Persons who live in or visit endemic regions who are also aware of the medical problems that C. immitis can produce may be more likely to seek medical attention when symptoms arise, resulting in earlier and more effective diagnosis and management.
Article and Author Information
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More information about coccidioidomycosis is available at http://www.arl.arizona.edu/vfce.
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Grant Support: In part by the U.S. Department of Veterans Affairs, the NIAID (National Institute of Allergy and Infectious Diseases) Mycoses Study Group (NO1-AI-65296), and the California Health Care Foundation.
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Requests for Reprints: John N. Galgiani, MD, Valley Fever Center for Excellence, 3601 South Sixth Avenue, Tucson, AZ 95723.
- Copyright ©2004 by the American College of Physicians
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