Coccidioidomycosis Overview and Associated Risk Factors
This section discusses the etiology, epidemiology, risk factors, and description of coccidioidomycosis infection and associated manifestations, as well as diagnosis and treatment options.
Etiology and Taxonomy of Coccidioidomycosis
Coccidioidomycosis (also called San Joaquin Valley Fever, Valley Fever, Cocci, Desert Rheumatism) is a mycotic fungal disease caused by 2 nearly identical species of the genus Coccidioides, specifically Coccidioides immitis and Coccidioides posadasii1021, 1067, 1044 and are referred to as the Californian and non-Californian species, respectively.1021 The Coccidioides species fall under the class Ascomycetes, and are genetically related to the pathogenic dimorphic fungi Histoplasma capsulatum, Blastomyces dermatitidis,1044 and Paracoccidioides.1067
Coccidioidomycosis Life Cycle
Coccidioides species are dimorphic
fungi with a saprophytic phase and a parasitic phase
Fig.147.1067, 1020 During the saprophytic phase the fungus lives in the soil as mold,
extracts nutrients from organic breakdown and decay, and develops
branching hyphae.1021, 1067, 1020 The fungus reproduces asexually through
disjoining of the hyphae into small (
Arthroconidia transform into thick-walled spherules
(pathognomonic for coccidioidomycosis) that contain hundreds to thousands
of uninucleate endospores. Spherules can grow up to
Figure 147 – Coccidioides Life Cycle
Kaiser, GE. Life cycle of the dimorphic fungus Coccidioides immitis. 1998. Available at: http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit3/fungi/u1fig39a.html. Accessed July 2, 2009.
Some figures may not display clearly when rendered as a PDF or printed.
Figure 148 – Life Cycle of Coccidioides Immitis
Figure 2, Page 16, PLoS Med (Public Library of Science) 2005;2:(1):e2-e5 is used with permission of the Public Library of Science.
Some figures may not display clearly when rendered as a PDF or printed.
Epidemiology of Coccidioidomycosis
The epidemiology of coccidioidomycosis, including its geographic distribution and population incidence, is described in the following sections.
Distribution
The Coccidioides species are found in the soil of the southwestern United States, Mexico, and Central and South America1021, 1067 between the latitudes of 42° North and 42° South.1044 This semi-arid area corresponds to a region referred to as the Lower Sonoran Life Zone. In the United States, coccidioidomycosis endemic areas include, most notably, western Texas, New Mexico, Arizona, southern Nevada, southern Utah, and central and southern California.1021, 1044, 1023 (See Fig.149.)
Figure 149 – Geographic Distribution of Coccidioidomycosis
Figure 1, Page 15, PLoS Med (Public Library of Science) 2005;2:(1):e2–e5 is used with permission of the Public Library of Science.
Some figures may not display clearly when rendered as a PDF or printed.
Incidence
Over the past 15 years, there has been a dramatic increase in the number of coccidioidomycosis cases leading some to propose that the disease is re-emerging or becoming an epidemic.1023 Outbreaks have been reported in California 1056, 1100, 1109, 1072 and Arizona 1046, 1058 during this period. However, the increase in documented cases of coccidioidomycosis may be due to several factors: surveillance for coccidioidomycosis in Arizona before 1995 was based on voluntary physician reporting, lack of clear case definition for coccidioidomycosis until 1995, and lack of mandatory reporting in Arizona until 1997.1023
In 1995, it was estimated that there were approximately 100,000 coccidioidomycosis infections per year.1115 By 2005, Galgiani, et al, estimated that 150,000 coccidioidomycosis infections were occurring annually, with the increase attributed to the rising populations in Arizona and California.1075 Migration, new construction, and climatic changes (exceptionally rainy conditions followed by a drought) are all considered factors leading to the increase in coccidioidomycosis infections.1021, 1067, 1023
Park, et al, 2005 (Environmental Factor Study)
In 2005, Park, et al,1023 published a retrospective review regarding the incidence of disease and hospitalizations related to coccidioidomycosis in Arizona. The authors analyzed the National Electronic Telecommunications System for Surveillance and the Arizona Hospital Discharge Database from 1998 to 2001. To calculate the denominators for rate calculations, they used 2000 US Census data as well as estimates for noncensus years and made adjustments for the annual statewide winter migration of 300,000 visitors. Furthermore, to examine the factors related to the increase in coccidioidomycosis infections, the authors conducted 2 additional studies. Specifically, they completed a cohort study of case patients to determine whether differences in recalled exposures or host factors were associated with periods of high vs. low incidence. They also conducted a climatologic study to examine whether changes in climatic or environmental conditions might have been related to the increased incidence in coccidioidomycosis infections in Maricopa County, Arizona.
Their findings illustrated that the annual incidence
of coccidioidomycosis in Arizona increased from
Park and co-authors’ cohort study indicated that known risk factors for coccidioidomycosis infection were not statistically more prevalent during periods of high vs. low incidence. Risk factors examined included the type of exposure during the month prior to illness (e.g., dust storm), diabetes, being immunocompromised, taking immunosuppressant medications, and/or smoking at illness onset.
The climatologic study found that drought indices,
wind, mean temperature, dust, and rainfall were all statistically
significant climatic and environmental variables. Using Poisson regression
modeling, Park, et al constructed a final prediction model that explained
75% of the variance
Figure 150 – Relationship Between Environmental and Climatic Variables and Coccidioidomycosis Cases in Maricopa County (1998-2001)
Table 1, Page 1986, J Infect Dis. 2005;191(11):1981-1987 is used with permission from the University of Chicago Press.
Some figures may not display clearly when rendered as a PDF or printed.
Park, et al, demonstrated a seasonal pattern of coccidioidomycosis in select groups, but did not find outbreaks to be related to population characteristics, exposure, or comorbidities. Likewise, adjusting for the annual elderly winter visitor migration did not account for outbreaks. Geographic Information Systems analysis revealed high age-adjusted coccidioidomycosis rates in areas undergoing a large amount of construction activity and development in the outskirts of the Phoenix metropolitan area. Fig.151 One proposed explanation for this geographic distribution was that these areas also have large retirement communities not previously exposed to coccidioidomycosis. Overall, these investigators found that climatic variables, including hot, dry conditions, had the strongest association with incidence, and that an important component of the epidemic in Arizona is the large disease burden of the elderly population.
Figure 151 – Average Annual Incidence of Coccidioidomycosis in Maricopa County, Arizona (1998-2001)
Figure 3, Page 1983, J Infect Dis. 2005;191(11):1981-1987 is used with permission from the University of Chicago Press.
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Risk Factors Associated With the Development of Coccidioidomycosis
Age is a significant risk factor for developing
coccidioidomycosis.1021, 1044 The highest risk appears to be in the elderly who recently
moved to endemic areas such as Arizona.1021, 1044, 1092 Other risk factors for developing severe, disseminated coccidioidomycosis
include immunosuppression either as a result of disease or treatment
with immunosuppressant medications.1067, 1044, 1075, 1050, 1105 Coccidioidomycosis is also frequently
a complication of human immunodeficiency virus (HIV) infection.1067, 1044, 1020, 1073, 1045, 1094, 1043, 1123 However, decreased incidence
of coccidioidomycosis in HIV-infected individuals has been noted since
the advent of highly active anti-retroviral therapy.1044 Solid organ transplant patients are also at increased risk,1067, 1044, 1075 as are those with diabetes.1021, 1050 Gender is
also a risk factor, with males having a
Although males are typically at higher risk for
developing disseminated coccidioidomycosis, pregnancy has long been
associated with increased susceptibility for developing coccidioidomycosis,
including severe, disseminated disease.1067, 1020 Research has shown that this increased
risk for disseminated disease is lower than previously reported but
is still higher than that found in the general female population of
childbearing years.1054 It has been theorized that the increased risk for severe coccidioidomycosis
in pregnant women is secondary to the immunosuppression that accompanies
gestation. However, another proposed mechanism is that progesterone
and 17 β-estradiol stimulate the growth of the spherule/endospore
phase of coccidioidomycosis.1067 This research has only been completed
According to Cox and Magee, “In no other mycosis is the racial predisposition toward developing severe, disseminated disease more conclusive.”1077 Specifically, African-Americans, Filipinos, Mexican-Americans, Native Americans, and Asians appear to be increasingly susceptible.1067, 1044, 1020, 1075 One criticism of early research on race and coccidioidomycosis was the failure to control for a major confounding variable: occupation. Members of these minority groups more frequently have occupations such as ranching, farming, or other outdoor vocations that increase their exposure to soil and dust, thereby increasing their risk of coccidioidomycosis infection. However, research following recent outbreaks, where exposure was less likely biased by occupation, has yielded findings supporting the race and infections risk association.1067
The risk of occurrence and dissemination of coccidioidomycosis
is greater in immunocompromised patients than non-immunocompromised
patients. Immunocompromised patients, including those with immune-mediated
inflammatory disorders and those with other immunocompromising conditions,
also have a higher risk of coccidioidomycosis whether or not they
are taking immunosuppressants. For instance, infection and dissemination
risk is greater in human immunodeficiency virus, Hodgkin’s disease,
and solid organ transplant patients than in non-immunocompromised
patients.1108, 1065, 1053, 1045 Cohen, et al, examined the incidence
of coccidioidomycosis in renallycompromised patients over a
Dissemination of coccidioidomycosis generally occurs in approximately 1% of patients and is sometimes thought to be a direct consequence of cellular immunity suppression.1069, 1071, 1099 There is 1 case in the medical literature describing a patient with Crohn’s disease (CD) who developed coccidioidomycosis and was not receiving immunosuppressive medications.1096 Although it is generally assumed that coccidioidomycosis does not infect the GI tract, CD results in the suppression of cellular immunity and could be a source of immunosuppression leading to disseminated coccidioidomycosis.1071, 1095
Clinical Manifestationsof Coccidioidomycosis
Coccidioidomycosis presents as a wide spectrum of illness, ranging from asymptomatic primary pulmonary infection that resolves without treatment to severe disseminated disease that can result in death. In general, there are 4 categories of coccidioidomycosis:
-
Primary Pulmonary Coccidioidomycosis
-
Valley Fever Complex
-
Chronic Pulmonary Coccidioidomycosis
-
Disseminated Coccidioidomycosis
Each category has different treatment and prognostic implications.1067
Primary Pulmonary Coccidioidomycosis
Early pioneering epidemiologic studies by C. E. Smith are credited with determining that approximately 60% of primary infections with Coccidioides are asymptomatic and only detectable through conversion of skin-test reactivity.1113, 1067, 1044, 1021, 1075 Almost all patients who acquire coccidioidomycosis, including those who are initially asymptomatic, resolve their infection and have lifelong immunity.1021, 1044, 1075 Nevertheless, there have been reports of reactivation in severely immunocompromised patients such as organ transplant recipients.1067
The remaining 40% of primary pulmonary infections exhibit mild flu-type symptoms, such as a limited acute or subacute pneumonia, that become apparent approximately 1 to 3 weeks post-infection.1075 Common symptoms include fever, chills, pleuritic chest pain, cough, headache, fatigue, arthralgia, and anorexia.1067, 1044, 1020 This type of presentation is often indistinguishable from a bacterial or other infection unless lab testing is performed, specifically, coccidioidal serologic testing or fungal culture.1075 Single or multiple pulmonary infiltrates are typically noted on chest radiographs and are frequently hilar or basal in location. However, atelectasis, hilar adenopathy, and pleural effusions occur in a minority of patients.1020 Ten to 30% of patients also develop an erythematous rash, usually within the first few days of clinical illness, that spontaneously resolves shortly thereafter in most cases. Termed toxic erythema, this rash typically covers the trunk and lower extremities and is attributed to the acute febrile illness.1067, 1020
Valley Fever Complex
Valley Fever or Valley Fever Complex occurs in approximately 5% of all primary infections and results in a combination of pulmonary symptoms with cutaneous evidence of a delayed-type hypersensitivity reaction. Specifically, erythema nodosum and erythema multiforme typify Valley Fever Complex and are the principal manifestations, though arthralgias (Desert Rheumatism) and conjunctivitis may also occur.1067, 1044 Valley Fever Complex typically occurs more often in females and is usually associated with a benign outcome.1044
Chronic Pulmonary Coccidioidomycosis
It has been estimated that 5% to 10% of primary coccidioidomycosis infections develop into chronic pulmonary coccidioidomycosis.1067, 1044 Manifestations of chronic pulmonary coccidioidomycosis include progressive pneumonia, miliary disease, pulmonary nodules, or pulmonary cavitation.1067 Chronic pulmonary coccidioidomycosis typically presents with a single pulmonary nodule that is benign and often difficult to distinguish from malignancy. Fig.152 Multiple or multilocular nodules can occur as well. In addition, pulmonary nodules may cavitate. The majority of nodules are asymptomatic and spontaneously resolve, though some patients develop chronic progressive pulmonary involvement, including symptoms of cough, chest pain, hemoptysis, weight loss, and dyspnea that may continue for years.1067, 1044 In these exceptional cases, radiographic findings include biapical fibronodular lesions, multiple cavities, and inflammatory infiltrates.1067
Figure 152 – Coccidioidomycosis Pulmonary Nodule
National Library of Medicine. Coccidioidomycosis: chest X-ray. Available at: http://www.nlm.nih.gov/medlineplus/ency/imagepages/1600.htm. Accessed July 18, 2008.
Some figures may not display clearly when rendered as a PDF or printed.
Disseminated Coccidioidomycosis
Dissemination results when an infection spreads outside the thoracic cavity.1044 Rates of primary coccidioidomycosis developing into disseminated coccidioidomycosis vary from 0.5% for Caucasians to several fold higher in those of African or Filipino ancestry.1075 African and Filipino ancestry, males, pregnant females, and the immunocompromised have an increased risk of dissemination.1067, 1020 Furthermore, dissemination rate is also dependent upon exposure, with those experiencing greater exposure (e.g., after an earthquake or dust storm) manifesting higher incidence.1067
Dissemination typically occurs early in the disease course and may present in the absence of clinical or radiologic findings indicative of former pulmonary infection. Exceptions, however, have been demonstrated, and dissemination can be acute, subacute, or chronic. Extrapulmonary infection can occur throughout the body, except in the GI tract.1096 Affected areas include the skin and subcutaneous tissues, bone, lymph nodes, spleen, kidneys, liver, meninges, or pleura.1067 Skin manifestations can include wart-like nodules, lesions, papules, verrucous plaques, abscess, pustules, and sinus tracts.1075, 1026 Skin and subcutaneous lesions occur in greater than 65% of disseminated coccidioidomycosis cases.1067 Bone involvement can include single and multiple lesions in the long bones, spine, hands, feet, and skull. Synovial involvement is evident through arthritic pain and joint swelling, particularly in the ankles and knees.1020
Coccidioidal meningitis presents in 30%50% of disseminated coccidioidomycosis cases, with affected patients typically presenting with headaches and decreased mental acuity.1067, 1044 The meninges may be the only site of extrapulmonary disease in some patients, and death is inevitable, usually within 2 years, despite treatment.1067 Single extrapulmonary lesions, except those in the meninges, typically denote a favorable prognosis. Overall mortality rate is greater than 50% in those with multifocal dissemination, and death occurs as quickly as 3 to 4 months in those with acute miliary dissemination.
Diagnosis of Coccidioidomycosis
Diagnosis can be made through a variety of methods that demonstrate the characteristic endosporulating spherules in exudate, tissue, and sputum; in specimens that culture Coccidioides immitis; or by serologic testing.1101, 1020 Chest radiograph and bone scan cannot distinguish coccidioidomycosis from other pulmonary diseases. Therefore, these methods are not useful in rendering a definitive diagnosis but may be useful in following disease progression and determining prognosis after a confirmatory diagnosis has been made via another method.1020
Culturing infected samples is an expedient method for diagnosing coccidioidomycosis and may yield positive results when histologic and cytologic results are negative. 1020, 1044 Coccidioides species grow quickly at 37°C on the proper media.1044 However, cultures are frequently negative in acute pulmonary coccidioidomycosis.1068 Respiratory secretions yield better results than cerebrospinal fluid (CSF) or blood cultures. CSF cultures are positive roughly 33% of the time, and blood cultures are typically negative except in severe cases of immunosuppression with significant pulmonary involvement.1020 Another disadvantage is that cultures require several weeks for speciation and final reporting.1078 Finally, the CDC lists Coccidioides species as Select Agents; hence, their growth in culture requires secure and contained handling as they are considered a biohazard.1020, 1044, 1075
Histopathologic methods, by staining with Gomori-methenamine-silver, hematoxylin-eosin, or Papanicolaou, are a sensitive way of identifying small numbers of spherules, although these methods can delay diagnosis and can rarely be used in CSF analysis.1020, 1044 The Papanicolaou stain is especially useful in detecting spherules in sputum or other respiratory samples.1044
Skin tests are no longer commercially available in the United States.1084, 1026 Moreover, these tests are typically not sensitive in the first few weeks after Coccidioides exposure. They also have limited usefulness because they measure exposure, but not active infection. Skin tests have decreased reactivity in the immunocompromised, as well as in immunocompetent patients with advanced disease. In addition, positive reactions designate exposure, whereas negative reactions do not rule it out. Serial testing also decreases the probability of yielding a positive reaction.1020
Serologic testing is the most commonly used method of diagnosing coccidioidomycosis.1044 It is recommended when infection is suspected as well as after detection via culture or microscopy because it allows monitoring of disease progression.1020 There are various serologic tests available including tube precipitin (TP), complement fixation (CF), immunodiffusion with heated coccidioidin (IDTP), and latex agglutination (LA).1028 These tests measure immunoglobulin G (IgG) and/or immunoglobulin M (IgM). During the early stages of newly acquired infection or dissemination, IgM antibodies are produced and detectable typically by the second week. Decline in IgM production usually begins approximately 6weeks,post-symptom onset and ends at approximately the same time IgG antibody production peaks.1020, 1028
The TP test was developed over 50 years ago by Smith1113 and is associated with an IgM response, which is indicative of new or relapsing infection.1028 The IDTP and LA tests measure IgM as well and have largely replaced the TP test. The IDTP test correlates well with the TP test, whereas the LA test renders more false positives.1068, 1028 Modifications to IDTP (e.g., counterimmunoelectrophoresis) yield antigen-antibody reactions within 2 hours vs. TP or IDTP, which require 18 to 24 hours to develop.1101
CF testing detects IgG antibody production and
is considered by many to be the most important serologic test for
coccidioidomycosis.1068, 1028 IgG titers are related to disease severity. Therefore, CF
testing is not only useful for disease detection, but also for determining
disease severity (a rising titer between
Enzyme-linked immunosorbent assay (ELISA) techniques
for coccidioidal antigens allow coccidioidomycosis to be diagnosed
in the early stages of disease before detection of IgM and IgG with
complement fixation. A
Polymerase chain reaction is a newer approach to detecting coccidioidomycosis that appears sensitive and rapid, although additional research is warranted.1020
Treatment of Coccidioidomycosis
Coccidioidomycosis is a continuum of disease. At one end of the spectrum, coccidioidomycosis may result in asymptomatic infection, mild respiratory syndrome, or uncomplicated pneumonia that spontaneously resolves with supportive care. Conversely, coccidioidomycosis can result in progressive pulmonary destruction or disseminated lesions in other parts of the body, including the meninges. Consequently, management strategies need to be tailored and may vary considerably.1075, 1076
Galgiani, et al, published thorough practice guidelines for coccidioidomycosis treatment1076 , and in 2005 published an updated version of these guidelines that was endorsed by the Infectious Disease Society of America.1075 For a comprehensive review of treatment options and standard of care treatment guidelines, the reader can review Galgianis’ publication,1075 but should also consult an infectious disease specialist when managing any risks or cases of infection. The products described in the following sections include only treatments approved by the FDA for coccidioidomycosis.
There are 2 classes of anti-fungal therapy used
to treat coccidioidomycosis, the polyenes and the azoles.1075, 1021, 1044 The polyenes include
Ketoconazole is an azole anti-fungal that is also indicated
for the treatment of coccidioidomycosis. The recommended dosage of
oral ketoconazole is
Primary Pulmonary Coccidioidomycosis
Smith, et al, are credited with determining that approximately 60% of primary infections with Coccidioides are asymptomatic, only detectable through a conversion of skin-test reactivity, and that the majority of primary pulmonary Coccidioides infections spontaneously resolve with supportive care alone.1113, 1021 Therefore, they suggest that no anti-fungal therapy may be warranted in many cases. However, these authors also suggest that the clinician should routinely follow-up with the infected patient every 3 to 6 months over a period of 2 years if no therapy is given. During these visits, it is recommended that repeat radiographic studies be completed to either demonstrate resolution or to identify illness exacerbations, such as pulmonary or extrapulmonary complications, as quickly as possible.1075
Despite published treatment guidelines1075, 1076 that no therapy is required for most cases of primary pulmonary coccidioidomycosis and that treatment should be reserved for those with persistent primary illness, chronic pulmonary disease, or extrapulmonary dissemination, physicians are increasingly prescribing azole anti-fungal therapy for patients with primary pulmonary coccidioidomycosis infection.1021, 1075, 1044
Supportive care is the standard of care when
treating primary pulmonary infection. However, there are special circumstances
that warrant therapy with an oral azole anti-fungal at dosages of
Chronic Pulmonary Coccidioidomycosis
Treatment recommendations vary for cases of chronic
pulmonary coccidioidomycosis based upon severity, chronicity, extent
of the pneumonia, the presence or absence of pulmonary nodule(s),
whether cavitation has occurred, and whether the cavity is asymptomatic,
symptomatic, and/or ruptured. In cases of diffuse pneumonia with bilateral
reticulonodular or miliary infiltrates,
According to Galgiani,1075 anti-fungal therapy is unnecessary in cases where there is a stable pulmonary nodule. Likewise, the Infectious Diseases Society of America advises that if the lesion is resected and diagnosis rendered from the excised tissue, anti-fungal therapy is not recommended. Enlargement of the nodule warrants re-evaluation and consideration for therapy if active infection is found.1075
Asymptomatic pulmonary cavities are often benign and do not warrant treatment. There is no evidence that anti-fungal therapy has a beneficial impact on asymptomatic coccidioidal cavities. Cavities should be monitored over time. Resection is warranted in cases where the cavity becomes progressively enlarged, is immediately adjacent to the pleura, or if it is still detectable after 2 years.1075
Symptomatic cavities are often treated with azole anti-fungal treatment, although symptom recurrence upon treatment discontinuation is common. Treatment for several weeks with an oral antibacterial is warranted if a bacterial superinfection is present. These therapies, however, typically do not result in cavity closure. Hence, resection may be recommended, as opposed to chronic or intermittent anti-fungal therapy, in cases with low surgical risk to definitively resolve the problem.1075
Coccidioidal cavity rupture into the pleural
space rarely occurs but may necessitate surgical closure by lobectomy
with decortication. Anti-fungal therapy is recommended, especially
for those with delayed diagnosis or comorbid disease.
Disseminated (Extrapulmonary) Coccidioidomycosis
According to a review by Galgiani,1075 treatment of disseminated coccidioidomycosis depends on whether
there are single or multiple extrapulmonary nodules, miliary dissemination,
and meningeal vs. no meningeal involvement. Oral azole anti-fungal
therapy is usually the initial therapy. If there is rapid worsening
of lesions or if they are located in critical locations,
There is no therapy approved by the FDA for coccidioidal meningitis. Infectious disease specialists and guidelines1076 should be consulted for the most appropriate treatment as well as associated risks.
Prophylaxis Against Coccidioidomycosis
There is no therapy approved by the FDA for the
prophylaxis of coccidioidomycosis in immunocompromised patients. However,
a publication has reported results in organ transplant patients.1075 Prophylactic anti-fungal treatment in human immunodeficiency
Content on this page was last reviewed on March 05, 2009.
Content on this page was last changed on March 25, 2009.
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