Coccidioides immitis

I. Organism Information

A. Taxonomy Information
  1. Species:
    1. Coccidioides immitis (Website 1):
      1. Ontology: UMLS:xxx
      2. GenBank Taxonomy No.: 5501
      3. Description: Coccidioidomycosis was originally described by Alehandro Posadas (and later confirmed by Robert Wernicke) from a soldier, Domingo Ezcurra, who acquired this infection in the Argentine pampas (1892). Posadas and Wernicke recognized the presence of an organism, likened to a protozoan of the order Coccidia. Formal description of C. immitis was performed by Rixford and Gilchrist from a case observed in California (1896). However, the parasite was then still thought to be a protozoan. The correct taxonomic status of C. immitis as an ascomycete fungus was demonstrated by Ophuls and Moffit (1900) by culture on artificial of the fungal mycelia using arthrospores isolated from laboratory infections of guinea pigs. The etiological relationship between C. immitis and coccidioidomycosis was also demonstrated by showing that arthroconidia cause infection in several types of laboratory animal. The lack of any known meiosporic state in vitro or in vivo hampered further classification until work by Sigler and Carmichael (1976) recognized the similarity between the asexual spores (arthroconidia) of C. immitis and those (aleurioconidia) found in the mitosporic genus Malbranchea Sacc., placing C. immitis in the order Onygenaceae. This relationship was confirmed by molecular phylogenetic methods (1996), and Uncinocarpus reesii Sigler and Orr was shown to be the sister group to C. immitis (Fisher et al., 2002).
      4. Variant(s):
B. Lifecycle Information :
  1. Stage Information:
    1. Mold: (Kirkland and Fierer, 1996):
      1. Shape: Colony Morphology: At first, it is moist, glabrous, and grayish, but the colony rapidly develops abundant, floccose, aerial mycelium that soon covers the slant. The mycelium is initially white, but usually becomes tan to brown with age (Rippon, 1988).
      1. Description: Conidiation begins within a few days after the initiation of growth. The conidia usually appear first on side branches of the vegetative hyphae. The hyphae themselves are thin and septate, but the side branches are almost twice as thick and have numerous septations (Rippon, 1988).
    2. Arthroconidia: (Kirkland and Fierer, 1996):
      1. Size: 2.5 to 4um by 3 to 6um (Rippon, 1988)
      1. Shape: Barrel shaped (Rippon, 1988)
      1. Description: Thick-walled arthroconidia are then produced, alternating with thin-walled empty cells (disjunctors). The arthroconidia are barrel-shaped 2.5 to 4um by 3 to 6um in size, and are released by fragmentation of the mycelium. They retain portions of the walls of the disjunctor cells as ornaments on the walls of either end. This characteristic is often helpful in distinguishing the species. As the culture ages, the vegetative hyphae also fragment into arthronconidia. No other type of conidia formation is seen in culture of this fungus (Rippon, 1988).
    3. Spherule: (Kirkland and Fierer, 1996):
      1. Size: 30 to 60um in diameter (Rippon, 1988)
      1. Shape: Round (Rippon, 1988)
      1. Description: They become more rounded as they transform into spherules. At maturity, these are 30 to 60 um in diameter. The wall is thick (to 2um) and quite prominent. The cytoplasm is eosinophilic and contains many nuclei. As the spherules near maturity, endospore production begins by a process called ?progressive cleavage.? (Rippon, 1988)
    4. Endospore: (Kirkland and Fierer, 1996):
      1. Size: 2 to 5um in diameter (Rippon, 1988)
      1. Shape: Round (Rippon, 1988)
      1. Description: Secondary cleavage lines are formed, which divide the contents of the spherule into uninucleate endospores that are 2 to 5um in diameter. At maturation, the spherule wall breaks and the endospores are released (Rippon, 1988).

  2. Progression Information:
    1. Arthroconidia release -- From stage: Mold , To stage: Arthroconidia:
      1. Description: As the mycelial strands mature, barrel-shaped arthroconidia form, which disarticulate, become airborne, and are returned to the soil or inhaled (Stevens, 1995).
    2. Spherule formation -- From stage: Arthroconidia , To stage: Spherule:
      1. Description: Following inhalation, the arthroconidium develops into a spherule, within a few hours or days (Rippon, 1988).
    3. Endosporulation -- From stage: Spherule , To stage: Endospore:
      1. Description: As the spherules near maturity, endospore production begins by a process called ?progressive cleavage.? Furrows form and divide the protoplasm into multinucleate masses called ?protospores.? Often there is a central vacuole in the spherule. Secondary cleavage lines are formed, which divide the contents of the spherule into uninucleate endospores that are 2 to 5um in diameter. At maturation, the spherule wall breaks and the endospores are released. The surviving spores gradually evolve into spherules, and the process is repeated (Rippon, 1988).

  3. Description: Coccidioidomycosis is caused by Coccidioides immitis, a dimorphic fungus that grows as a mold in the soil. The mold forms arthroconidia within the hypha, a type of conidia formation known as enteroarthric development. C. immitis is the only species within the primary pathogenic fungi that has this type of conidia development. Alternate conidia undergo autolysis, leaving empty spaces between viable arthroconidia. The arthroconidia are released into the atmosphere when the wind ruptures the hypha. C. immitis infects humans and animals almost exclusively by the respiratory route. Once inhaled, the arthroconidia cluster in the lungs and undergo a dramatic morphologic change. The round cells, which develop into spherules, undergo repeated internal divisions until they are filled with hundreds to thousands of offspring, termed endospores. This process occurs over 48 to 72 hours. When the spherule ruptures, each released endospore has the capacity to develop into a mature spherule (Kirkland and Fierer, 1996). We conclude that biparental sex is a regular part of the C. immitis life cycle, at least in our study population. This study is, to our knowledge, the first to find molecular evidence for recombination in a fungus for which no sexual stage has yet been described. These results motivate a directed search for mating and meiosis, as the ability to cross isolates would greatly facilitate genetic studies of this human pathogen (Burt et al., 1996).
  4. Lifecycle of Coccidioides immitis (Kirkland and Fierer, 1996):



    Description: **PERMISSION NOT YET GRANTED**The dimorphic life cycle of Coccidioides immitis (Kirkland and Fierer, 1996)
C. Genome Summary:
  1. Genome of Coccidioides immitis RS (Coccidioides Sequencing Project Website):
    1. Description: The Coccidioides immitis sequence project is part of the Broad Institute's Fungal Genome Initiative. Its goal is to release a 10X genome sequence coverage for Coccidioides immitis, strain RS. Genomic DNA for C. immitis was contributed by Theo Kirkland and Suganya Viriyakosol at University of California San Diego, School of Medicine, Department of Pathology. Broad Institute produced whole genome shotgun sequence from 4kb and 10kb plasmids and 40kb Fosmids. The resulting 10X assembly was made public April 2004. Data releases: July 2004 - Release 1 consists of a 10X whole-genome shotgun assembly generated at the Broad Institute, available for download and BLAST searches. Release 2 will provide the results of automated genome annotation (Coccidioides Sequencing Project Website).
    2. 10X whole-genome shotgun assembly:
      1. GenBank Accession Number: CH379576,CH379577,CH379578,CH379579,CH379580,CH379581,CH379582,CH379583,CH379584,CH379585,CH379586
      2. Size: 29 Mb (Coccidioides Sequencing Project Website-FAQ)
      3. Description: ADDITIONAL DATA: 10X sequencing coverage of the genome; 215 contigs longer than 2 Kb; 20 supercontigs; 133.8 Kb average contig length (range 2.0 - 794.5 Kb); 1.4 Mb average supercontig length (range 3.0 Kb - 7.9 Mb); 28.8 Mb total length of combined contigs (28,777,468 bp); Average base lies in a contig of length 251.8 Kb; Average base lies within a supercontig of length 3.9 Mb; (Coccidioides Sequencing Project Website)

II. Epidemiology Information

C. immitis is primarily found in desert soil. It is present in highest numbers in the San Joaquin Valley in California, southern Arizona, southern New Mexico, west Texas, and the desert areas of northern Mexico. The organism is also found in scattered foci in coastal southern California, southern Nevada, and Utah and is endemic in a few areas in Central and South America, especially in Venezuela. C. immitis is distributed unevenly in the soil and seems to be concentrated around animal burrows and ancient Indian burial sites; it is usually found 4 to 12 inches below the surface of the soil. Since C. immitis infects humans by the respiratory route, exposure to dust is one critical factor determining the risk for infection. Coccidioidomycosis is not spread from person to person, except in extraordinary circumstances. Coccidioidomycosis probably had its most profound effect on the population of the United States during World War II when several training airfields were built in the San Joaquin Valley. The rate of new infections in military personnel was 8% to 25% per year. Coccidioidomycosis was the most common cause of hospitalization at many airbases in the Southwest. Though the death rate was very low, many soldiers were sick for weeks to months, and their training was completely disrupted. At least in part because of efforts to minimize dust, the infection rate declined as the war went on. The incidence of coccidioidomycosis varies with the season; it is highest in late summer and early fall when the soil is dry and the crops are harvested. If it rains at this time of the year (which is unusual in southern California), disease incidence declines as the amount of dust decreases. Dust storms are frequently followed by outbreaks of coccidioidomycosis. One particularly severe dust storm in 1977 carried dust from the San Joaquin Valley up to the San Francisco Bay area and resulted in hundreds of cases of nonendemic coccidioidomycosis in areas north of the San Joaquin Valley. More recently, an earthquake centered in Northridge, California, was associated with 170 cases of acute coccidioidomycosis in Ventura County, which normally has a low incidence of this disease. The airborne dust associated with landslides triggered by the earthquake was implicated in the increase in the number of cases. Occupational or recreational exposure to dust is also an important consideration. Agricultural workers, construction workers, or others (such as archeologists) who dig in the soil in the disease endemic area are at increased risk for the disease. During World War II, C. E. Smith, one of the most perceptive and influential epidemiologists to study coccidioidomycosis, recommended dust control as a primary measure to reduce risk for exposure. However, because the desert is inherently dusty, many cases of coccidioidomycosis are acquired just by driving through the disease-endemic area (Kirkland and Fierer, 1996).

A. Outbreak Locations:
  1. Coccidioidomycosis is endemic in California. In an 11-year period from the beginning of 1980 to the end of 1990, an average of approximately 400-500 cases per year were reported to the California State Department of Health Services (CSDHS). In 1990, 441 cases were reported. However, a striking increase in the number of cases was noted in 1991, 1992, and 1993, particularly in the southern San Joaquin Valley counties of Kern and Tulare. In 1992, striking increases were noted in other counties as well. In California there were 1,200 and 4,541 new cases in 1991 and 1992, respectively, that were reported to the CSDHS. The usual rate (5%-7%) of metapulmonary dissemination was noted in these outbreaks, and cases resembling acute adult respiratory distress syndrome that had been noted infrequently in previous outbreaks were conspicuous among the 1991 and 1992 cases. Factors thought to contribute to the extraordinary increases in coccidioidomycosis were a drought of 5 to 6 years' duration; abundant rain in March 1991 and February-March 1992; construction of new buildings; and arrival of new, susceptible individuals to the areas of endemicity (Pappagianis, 1994).
  2. Early in the morning on December 20, 1977, high-velocity winds centered around Arvin, a town in the southern extreme of the San Joaquin Valley near Bakersfield, in Kern County, California, bore aloft soil containing arthroconidia of Coccidioides immitis. Dispersion of this soil by peculiar wind conditions resulted in an epidemic of coccidioidomycosis in an area encompassing approximately 87,00 square km, an area larger than the stated of Maine. We report the morbidity, mortality and cost of the epidemic in Sacramento County, an area of 2792 square km at the northern limit of the San Joaquin Valley, which is normally an area of low endemicity for coccidioidomycosis. The State of California Department of Health Services recorded approximately 550 cases of coccidioidomycosis in the first 16 weeks of 1978, as compared with a maximum of 175 for this period in any of the previous 10 years. The steep rise in cases from the fourth to the 18th weeks of 1978 reflects cases reported after the dust storm. The rate of rise resumed a slope similar to that in previous years at approximately the 18th week. Sacramento County reported 139 cases that probably resulted from exposure to the dust, in contrast to the zero to six cases reported per year over the previous 20 years. One hundred and fifteen of these 139 cases met our criteria for dust-storm-related coccidioidomycosis. Six of the 115 persons who acquired acute coccidioidomycosis as a result of infection with C. immitis during the dust storm have died (Flynn et al., 1979).
  3. On January 17, 1994, at 4:30am (Pacific standard time), a magnitude 6.7 earthquake occurred in the Northridge/Reseda area in Los Angeles County, California. The main shock and aftershocks resulted in 72 fatalities and assessed damage costs estimated at $23.8 billion. Ventura County, a coastal county northeast of Los Angeles County, has not been recognized as an area where coccidioidomycosis is highly endemic. Fewer than 60 cases were reported annually in 1992 and 1993, with peak reporting occurring in the late fall and winter months. However, in the first 5 weeks following the earthquake, 20 coccidioidomycosis cases were reported to the Ventura County Health Department, which was more than expected for that time period. Persons who reported being physically in a dust cloud generated by landslides following the earthquake or aftershocks were 3 times more likely to be diagnosed with acute coccidioidomycosis than those persons who did not report being physically in a dust cloud. Risk increased with reported duration of exposure to a dust cloud (Schneideret al., 1997).
  4. In July 1996 the Washington State Department of Health (Seattle) was notified that at least 15 persons from a church group, including many adolescents, had developed an unidentified, rash-associated, flulike illness. One of these cases was eventually recognized as coccidioidomycosis. The group had recently returned from a 6-day stay at an orphanage <15 miles south of Tecate, Mexico, a town in the Sonoran Desert adjacent to the United States?Mexico border. To determine the extent of the outbreak and risk factors for disease, we conducted an investigation (Cairns et al., 2000). One hundred twenty-six church group members participated in the trip to Tecate, which occurred from 8 to 13 July 1996. Of 100 members (79%) who were contacted, 59 (47% of 126) completed questionnaires, underwent skin tests, and had the results read (Cairns et al., 2000). Twenty-seven (46%) of the 59 church group members had a positive skin test. Serological testing for 21 of these members was positive for C. immitis (Cairns et al., 2000). Of the 21 members who met the case definition, 20 (95%) were adolescents aged 14?18 years (median, 16 years; range, 14?43 years), and 18 (86%) were female. Four patients (19%) had negative skin tests (Cairns et al., 2000).
  5. On December 4, 2001, CDC was notified by the United Kingdom (UK) Public Health Laboratory Service (PHLS) of a UK resident aged 72 years who had culture-confirmed coccidioidomycosis (i.e., Valley fever) diagnosed in early December. During October 8?12, the patient had attended the world championship of model airplane flying in Lost Hills, California, located in Kern County in the Central Valley of California, an area where coccidioidomycosis is highly endemic. The patient had influenza-like symptoms on approximately October 25, 1 week after returning from Lost Hills. CDC, in collaboration with UK PHLS and the California Department of Health Services, is conducting an investigation (MMWR, 2001b).
  6. Dinosaur National Monument (DNM) encompasses 320 square miles in northeastern Utah and northwestern Colorado; 397,800 persons visited DNM in 2000. On June 18, 2001, under the direction of National Park Service (NPS) archeologists, six student volunteers and two leaders began work at an archeologic site in DNM. Work included laying stone steps, building a retaining wall, and sifting dirt for artifacts. Peak dust exposure occurred on June 19, the day most sifting occurred. Workers did not wear protective facemasks. During June 29?July 3, all eight team members and two NPS archeologists who had worked at the site sought medical care at a local hospital emergency department for respiratory and systemic symptoms. All 10 persons had diffuse pulmonary infiltrates on chest radiographs; eight were hospitalized with pneumonia of unknown etiology. Pending investigation, NPS closed the work site to all visitors and staff, and the TriCounty Health Department alerted the public. On July 2, the TriCounty Health Department, the Utah Department of Health, and CDC initiated an investigation to identify the risk factors, cause, and extent of the outbreak (MMWR, 2001a). Results of blood cultures from the hospitalized persons were negative for bacterial pathogens. Initial serologic tests were negative for antibodies to Francisella tularensis, Yersinia pestis, Mycoplasma species, Histoplasma capsulatum, and C. immitis. On further analysis, using serum specimens concentrated 3?5 fold in an assay that detects IgM antibodies (immunodiffusion tube precipitin), nine of the 10 acute serum specimens from patients contained IgM antibodies to C. immitis, confirming the diagnosis of acute coccidioidomycosis. All hospitalized patients were treated with fluconazole. The average length of hospital stay was 1.5 days (MMWR, 2001a).
  7. From 10 September to 27 October 2001, a group of 23 Navy SEALs from San Diego and Honolulu participated in a military training exercise near Coalinga, California, which is located 60 miles southwest of Fresno, in a C. immitis?endemic area within the San Joaquin Valley. During the 6-week training period, the men camped in tents on sandy soil, drove in open military vehicles, ran on poorly vegetated land, and occasionally dug holes to conceal themselves. During these activities, all men reported extensive dust exposure and none used protective measures, such as facemasks (Crum et al., 2002). Ten (45%) of 22 men had serologic evidence of a recent C. immitis infection. Complement fixation (CF) titers in case subjects ranged from <1:2 to 1:16. The sole Hispanic man in this training group developed coccidioidomycosis with a CF titer of 1:16. Of the 10 men with serologic evidence of recent infection, all reported symptoms consistent with a C. immitis infection. No one reported joint swelling, bone pain, or a rash consistent with erythema nodosum or erythema multiforme. The onset of symptoms in 8 of the 10 case subjects occurred during the last week of September or the first week of October, approximately 2?3 weeks after their arrival at the Coalinga training site. Two case subjects reported symptoms beginning during the first 2 weeks of November. Symptoms persisted for 2?63 days (median, 19 days), and 3 patients reported missing 1?3 work days (Crum et al., 2002).
  8. Early in the human immunodeficiency virus (HIV) epidemic, coccidioidomycosis was recognized as an opportunistic infection that caused significant morbidity and mortality among HIV-infected persons living in areas of endemicity. Recently, analysis of surveillance data from Arizona during 1990?1995 documented a substantial increase in the incidence of coccidioidomycosis. This increase in incidence disproportionately affected residents aged >65 years and HIV-infected persons. During the same period, the prevalence of AIDS in Arizona increased by at least 79%. Analysis of hospital discharge data from 1993 revealed that 98 HIV-infected persons were hospitalized with coccidioidomycosis in Arizona, constituting 10% of all HIV-related hospitalizations. One-third of these HIV-infected persons died, compared with 15% of HIV-infected persons hospitalized for other reasons. The majority of coccidioidomycosis cases in Arizona, as well as cases of HIV infection, are reported from 2 southern counties: Maricopa (population 2,611,327) and Pima (population 767,873). By January 1995, approximately 4000 HIV-infected persons were living in both counties. Previous studies suggest that up to 27% of HIV-infected persons in southern Arizona may develop symptomatic coccidioidomycosis each year and that between 5% and 10% develop disseminated disease. Before this study, the only identified risk factors for developing symptomatic coccidioidomycosis in these persons were a diagnosis of AIDS and a CD4 lymphocyte count <250 cells/mL (Woods et al., 2000).
  9. The 1991 Piau? outbreak of coccidioidomycosis involved three individuals. On August 31, 1991 a 38 year old Brazilian man, his 11 year old son; and a 24 year old cousin, all life time residents of the community of Oeiras in the state of Piau?, went into the nearby hills to hunt for nine-banded armadillos (Dasypus novemcinctus) accompanied by eight hunting dogs. Their search was successful for they had dug one out of its burrow and had it as the piece de resistance of the family?s dinner. In digging out their prey, the three hunters and their eight dogs inevitably were exposed to aerosols of dust. Nine days later, on September 9, 1991, all three humans became ill with symptoms that included fever, weakness, myalgia, cough (at first without sputum, later with sputum) and dyspnea. At the same time all of the dogs also became ill. Three of them died in a few days. At that time the men were hospitalized in Oeiras?s local hospital. Their x-rays showed pneumonia. After the second week, the 11 year old boy got better and recovered spontaneously from his acute illness. The two adults, however, continued to have severe pneumonia with bilateral infiltrates. Accordingly, they were transferred to the Infectious Disease Hospital in Teresina, the capital of Piau?, about 161 kms to the north. As of December 1999 all the three patients were healthy and active (Wanke et al., 1999).
  10. On Dec. 26, 1966, 2 families consisting of 10 persons went on an outing near Beeville, Texas. Family A (father, mother, 8-year-old boy, 6-year-old boy, and a 4-year-old boy) were residents of Beeville. Family B (father, mother, 18-year-old boy, 14-year-old boy, and 7-year-old girl) were residents of Perry, Oklahoma. The group, all in good health prior to that time, visited and excavation area used for road-grading materials. The adults engaged in target practice, later removing the spent bullets from the walls of the excavation. The children, during the course of play, retrieved the family dog, which had become entrapped in a rodent burrow in the excavation area. Within 5 to 10 days of the outing, 9 of the 10 persons developed a flu like illness, including fever, headache, malaise, myalgia, cough, chest pain, anorexia, and vomiting. In addition, several patients had erythema nodosum and erythema multiforme. Signs and symptoms were self-limited in all persons except the index case, persisting from 1 to 3 weeks. On the fifth day following exposure, the family dog developed an illness characterized by respiratory distress, anorexia, and lethargy. He died on the third day of illness. Eight soil samples were obtained from the excavation area (7 random samples and 1 from the rodent burrow in which the dog had been entrapped). Of these, only the sample from the rodent burrow was positive for C immitis (Teel et al., 1970).
B. Transmission Information:
  1. Ontology: UMLS:xxx From: Soil To: Humans (Homo sapiens)
    Mechanism: ENVIRONMENTAL: Infection by Coccidioides results after inhalation of dust containing arthroconidia (Rippon, 1988).

  2. Ontology: UMLS:xxx From: Humans (Homo sapiens) To: Humans (Homo sapiens)
    Mechanism: LAB ACCIDENTS: Numerous reports of laboratory-associated coccidioidomycosis are documented in the literature published prior to 1980. Although cutaneous infections from accidental inoculation are documented, most laboratory-associated infections are caused by inhalation of the infectious arthroconidia (Sewell, 1995).

  3. Ontology: UMLS:xxx From: Humans (Homo sapiens) To: Humans (Homo sapiens)
    Mechanism: VERTICAL: The placenta is thought to be impermeable to the coccidioidin spherule because of the large size (40 to 70 ?m) of the spherule. Moreover thrombotic and chronic granulomatous reactions in the placenta appear to wall off the infection from the villous circulation. In a comprehensive review by Spark of neonatal onset of coccidioidomycosis, no cases of neonatal coccidioidal disease resulting from transplacental spread or vertically acquired infection were identified. Conversely placental involvement was not identified in 12 reported cases of neonatal onset and death. Our second patient is the first reported case (to our knowledge) linking maternal disseminated disease, placentitis and neonatal onset of infection. This indicates that transplacental spread may occur rarely. The findings in the mother's placenta substantiate the usefulness of histopathology to establish a specific diagnosis. Whether vertical infection by C. immitis could have been prevented by cesarean section is unknown (Linsangan and Ross, 1999). Neonatal coccidioidomycosis, although rare, has been reported. Aspiration of infectious vaginal secretions during birth appears to be the major mode of transmission. Transplacental infection has been thought not to occur because extensive coccidioidal placentitis is found without transmission of disease to the fetus. We report a case of neonatal coccidioidomycosis in an infant delivered by cesarean section. There was no labor and fetal membranes were intact at birth, indicating intrauterine acquisition of Coccidioides (Charlton et al., 1999).

  4. Ontology: UMLS:xxx From: Humans (Homo sapiens) To: Humans (Homo sapiens)
    Mechanism: TRANSPLANTATION: A North Carolinian developed fatal coccidioidomycosis immediately after bilateral lung transplantation. The donor had previously traveled to Mexico, and the recipient had no travel history to an area where Coccidioides immitis is endemic. Immunosuppresive therapy of the transplant recipient likely reactivated latent Coccidioides infection in the donor lungs, leading to posttransplant coccidioidomycosis (Miller et al., 2004).

  5. Ontology: UMLS:xxx From: Equus caballus To: Humans (Homo sapiens) (Kohn et al., 1992):
    Mechanism: INHALATION OF ENDOSPORES: A 33-year-old white veterinary resident was referred to the University of California Davis Medical Center because of fever, skin rash, and loss of 10 lb in 12 days. As a resident in large animal medicine, the patient primarily took care of sick horses. As of 13 days before he became ill, he autopsied a 5-year-old quarter horse mare subsequently discovered to have disseminated coccidioidomycosis. As the patient gave no history of recent travel through, or activity in, a region endemic for coccidioidomycosis, it is probable that he was infected when he autopsied the horse. Although inhalation of Coccidioidal arthroconidia is the usual mode of infection, an autopsy source of arthroconidia was not found. Exposure of the patient to spherules - endospores of C. immitis was indubitable. Transdermal infection is implausible because the patient had no preexisting skin lesions, was not wounded at autopsy, and never developed the chancriform lesions characteristic of this route of infection. Infection by inhalation is supported by the certainty of generation of infected aerosols during dissection that discovered abscesses, especially, while bandsawing through a patellar abscess (Kohn et al., 1992).

C. Environmental Reservoir:
  1. Soil :
    1. Ontology: UMLS:xxx
    2. Description: The fungus proliferates readily on almost any type of sterile soil at the extremes of naturally occurring pH and temperature (Rippon, 1988).
    3. Survival Information: Growth is more luxuriant on rich soil than on poor. However, survival of the organism in soil with normal bacterial and fungal flora is greatly decreased. It appears that C. immitis is ill fitted to survive in competition with other soil microorganisms and indeed is inhibited by some. Egeberg et al. found that, in the soils particularly favored by C. immitis, the most important inhibitory organisms were Bacillus subtilis and Penicillium janthinellum. These species proliferate during the rainy season, but as the temperature increases and evaporation increases salinity of the soil, their growth is inhibited. B. subtilis is sensitive to high salt concentration, and P. janthinellum to a temperature of 100F. C. immitis is very tolerant of a wide range of salt concentrations and almost uniquely tolerant to boron-containing salts. Growth also occurs up to a temperature of 130F. Both spherules and arthroconidia survive for long periods under adverse conditions, although the arthroconidia survive extreme conditions much longer. It appears, then, that the factors that delineate the ecologic areas inhabited by C. immitis are dependent upon the tolerance of the fungus to adverse soil composition and high temperatures, which are inhibitory to competing organisms (Rippon, 1988).
D. Intentional Releases:
  1. Intentional Release information :
    1. Description: C. immitis could be used as a weapon of bioterror or biowarfare with aerosol delivery. Its use for this purpose would, however, present a number of obstacles and its effect would be uncertain and most probably limited (Deresinski, 2003).
    2. Delivery mechanism: C. immitis conforms to some of the suggest characteristics of an ideal biological weapon, including ease of procurement, simplicity and low cost of production, ease of dissemination (at least on a small scale), and possibly, the potential to overwhelm a medical system by a large number of casualties. However, the difficulties in weaponization, as well as in control and dissemination of an airborne pathogen, are many and are not easily overcome. These include the need for production of nonclumping particles of appropriate size that are stable during aerosolization, and uniform distribution of an adequate number of arthroconidia. Furthermore, the lack of a safe and effective vaccine, although leaving a targeted population without an immunologic means of prophylaxis, also leaves the individuals producing the weapon and disseminating it without access to this means of protection. In the absence of a vaccine, however, it may be possible for the perpetrators to protect themselves by taking antifungal agents for prophylaxis. Line source contamination, as by an aircraft, is said to be the most effective means of delivery of a biological warfare agent, but this method is highly susceptible to meterologic conditions. Thus, changes in barometric pressure, rain, and wind are among the many factors that will affect dispersal of an airborne agent. Optimal conditions include a pressure inversion, no wind, and limited ultraviolet radiation. In consequence, as with other agents spread by aerosol, a small attack would be relatively easy to accomplish, but a large-scale attack would be much more difficult because of the problems of dispersal within and limited to the targeted area (Deresinski, 2003).
    3. Containment: Because human-to-human or animal-to-human aerosol transmission does not occur, quarantine is of no value. Exposed individuals could be given a drug such as fluconazole while still in the incubation period. There is, however, no data showing the effectiveness of such an approach. In most instances, coccidioidomycosis is a treatable infection. The vast majority of cases of symptomatic infection resolve without treatment, although it is possible that chemotherapy may shorten the duration of illness. If soil were to become persistently contaminated, the risk to individuals working in the area could be diminished by keeping dust levels to a minimum and the wearing of masks capable of preventing entry of arthroconidia. Decontamination of small areas of soil has been suggested. C. immitis is susceptible to 1% sodium hypochlorite, phenolics, glutaraldehyde, 1-chlor-2-nitropropane, and formaldehyde; its susceptibility to 70% ethanol is said to be questionable. Formaldehyde has been used to decontaminate sites at which epidemiologics of histoplasmosis have occurred. The toxicity of formaldehyde for humans, however, makes its use problematic. Iodophors, phenols, formaldehyde, and hypochlorite have been used to decontaminate laboratory surfaces. The most profound effect of an attack using C. immitis is likely to be psychologic. Immediate efforts to accurately and honestly inform the population of their risk would be the most critical part of any response to an attack using this organism (Deresinski, 2003).

III. Infected Hosts

  1. Humans (Homo sapiens):
    1. Taxonomy Information:
      1. Species:
        1. Humans (Website 3):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9606
          • Scientific Name: Homo sapiens (Website 3)
          • Description: Coccidioides is a formidable pathogen, capable of causing progressive pulmonary and/or disseminated disease in previously healthy individuals. Humans acquire the infection by inhalation of the arthroconidia, which differentiate into large, endosporulating spherules once they are in the host (Cox and Magee et al., 2004).

    2. Infection Process:
      1. Infectious Dose: < 10 arthroconidia by inhalation: Studies in mice have demonstrated the ability of only a few arthroconidia given intranasally to cause infection (Chiller et al., 2003).
      2. Description: Given the size of the arthroconidia (< 10um), they are easily able to escape the first-line defenses of the respiratory tract (filtration, mucocilliary transport, and mucoid chemical inhibitors) and reach the terminal bronchus (Chiller et al., 2003).

    3. Disease Information:
      1. Valley Fever (i.e., Coccidioidomycosis) :
        1. Pathogenesis Mechanism: The initial host response targets the arthroconidia and is characterized by and influx of polymorphonuclear leukocytes, which seem to be responding to chemotaxins generated in response to complement activation. Within the first 72 hours, arthroconidia convert to spherules and the inflammatory response changes to a mononuclear cell infiltration, which persists throughout infection and where the formation of granulomata may occur. Subsequent release of endospores from spherules produces a transient polymorphonuclear leukocytes response, presumably triggered by substances released from the rupturing spherule. The ability of spherules to resist host defenses has been noted by the inability of polymorphonuclear leukocytes to kill mature spherules in vitro. During the early stages of infection, the host?s specific immune response helps to determine the ultimate outcome and severity of the infection. It is clear that a cellular or TH1-type immune response is associated with control of infection. Studies have shown that the TH1 cytokine, interferon-gamma, has been associated with protective immunity in experimental murine infection. On the other hand, a limited cellular response characterized by a TH2-type immune response with elevated levels of antibody and IgE have been associated with worsening disease and dissemination. Studies support these findings, where the TH2 cytokine interleukin-4 is associated with an impaired immune response in mice. In patients, conditions where there are defective cellular immune responses, such as AIDS, late states of pregnancy, or during cytotoxic chemotherapy, have been associated with a higher risk of developing disseminated disease. The mechanisms by which virulence is conferred on C. immitis are still not well understood. Endospore products, such as urease and serine proteinases, probably play a role in the pathogenesis of the infection. Proteases may serve to digest antibodies and other opsonins. An enzyme with elastase activity seems to aid in breaking down the connective tissue matrix in the lung and helps spread the organism and destroy pulmonary parenchyma. This process also leads to increase cellular inflammation and possible further parenchymal destruction (Chiller et al., 2003).


        2. Incubation Period: 10 to 16 days (extremes: 7 days to 4 weeks): Following exposure and an average incubation period of 10 to 16 days, they become mildly ill with a ?cold? or may have severe respiratory disease. The extremes of the incubation period are seven days to four weeks, and the duration of the primary disease is from a few days to several weeks (Rippon, 1988). Most symptomatic patients have a febrile respiratory illness beginning 7 to 21 days after exposure (mean incubation time is 10-16 days) (Feldman and Snyder, 2001).


        3. Prognosis: Most symptomatic patients have a febrile respiratory illness beginning 7 to 21 days after exposure (mean incubation time is 10-16 days). The clinical features of the initial illness are usually nonspecific and mimic other respiratory tract infections. They include cough, chest pain, fever, and fatigue. The usual clinical course of primary Coccidioidal pneumonia is resolution and 76% of patients in this study went on to complete recovery from the infection (Feldman and Snyder, 2001). Recovery from primary disease occurs in almost all symptomatic and asymptomatic cases. Therefore primary disease is treated with bed rest and restriction of activity. Exceptions to this are manifest in one of the three major categories that predispose to a serious clinical course: race, pregnancy, and immunosuppression. In addition to bed rest, steroids are sometimes used to control severe allergic manifestations of uncomplicated primary infection, but patients so treated should be closely watched, as steroids may promote dissemination. Surgical intervention should be considered in benign residual disease of the lung because of the danger of recurrent hemoptysis. Cavities sometimes close spontaneously, however. All other forms of secondary coccidioidomycosis have a grave prognosis unless specific chemotherapy is instituted (Rippon, 1988).


        4. Diagnosis Overview: One of the best tests ever produced for a fungal infection is the serological test for coccidioidomycosis. This was originally developed by C. E. Smith, and the laboratory at the University of California, Davis has now done well over 100,000 serology tests. The patterns of this test are well described. The so-called precipitating antibody, which is an IgM antibody, appears early, so its presence is an indication of the acuteness of the infection. Over the first few months after primary infection, the CF antibody gradually appears and peaks in about 70% of patients. It is an IgG antibody and can be detected by immunodiffusion as well. It does not disappear if the patient develops disseminated disease. Coccidioidal serology is also valuable in that it inversely follows response to therapy, and thus can be used prognostically. If a patient under treatment has a falling CF antibody titer, that is a good sign. The reverse is also true. When the antibody titres are rising, then therapy should be intensified or changed. In addition, the titre is helpful in distinguishing patients who have localized versus disseminated disease. With titration performed by this standard method, titres of 1:16 to 1:32 or more are associated with disseminated disease (with the possible exception of patients with meningitis only, where the elevation of titres is not so clear-cut). These elevated titres may appear before there is any clinical evidence of dissemination, thus prodding the clinician to an aggressive diagnostic work-up. Thus, the serology of coccidioidomycosis provides a wealth of information about the patient being treated. Culture and histopathological strains remain valuable tools. A mould growing in the laboratory, suspected of being Coccidioides, can be identified in < 3 h by a DNA probe (Stevens, 2002).


        5. Symptom Information :
          • General Description: Approximately 60% of individuals who are infected with C immitis remain asymptomatic. The other 40% usually present with a mild to moderate influenza-like illness, including symptoms of cough, fever with drenching night sweats, or pleuritic chest pain. Arthralgias and myalgias may be prominent and are the reason for the synonym of ?desert rheumatism.? Rashes (erythema multiforme or erythema nodosum) may be seen. Systemic symptoms of fatigue, weakness, and anorexia are also common. Abnormal chest radiographic findings are seen in up to half of the symptomatic patients. Typically, infiltrates are associated with ipsilateral hilar adenopathy, although many other patterns are possible. Peripneumonic pleural effusions also may occur, and occasionally are very large. Most symptoms generally clear within 2 to 3 weeks. Some patients may take many weeks to months before all their symptoms, especially fatigue, resolve. Approximately 5% of patients develop residual pulmonary lesions or complications and less than 1% develops extrapulmonary disease. Although this is a small portion of the total patients infected, these patients are overrepresented in clinical practice, especially outside the endemic areas (Chiller et al., 2003). Extrapulmonary manifestations of coccidioidomycosis are almost always caused by dissemination due to hematogenous spread of the fungus. There does seem to be asymptomatic dissemination as demonstrated by the recovery of C. immitis from the urine of patients with isolated pulmonary disease. Patients usually manifest symptoms of extrapulmonary disease a few months after the primary infection. These are widely diverse, depending on the site of dissemination, and may involve multiple sites (Chiller et al., 2003).
          • Syndrome -- Asymptomatic pulmonary Disease:
            • Description: Asymptomatic Pulmonary Disease includes the majority of patients who become infected. There are no symptoms or at least none significant enough to have been remembered by the patient. Such patients are the ?skin test convertors? who become reactive to intradermal injections of coccidioidin in the absence of demonstrable disease. There is no residual scar or lesion in the lungs, and it is only the conversion to coccidioidin sensitivity that indicates an infection has occurred (Rippon, 1988).
            • Observed: Most common manifestation of infection (Rippon, 1988)
          • Syndrome -- Symptomatic Pulmonary Disease:
            • Description: Symptoms vary considerably in this group of patients. Following exposure and an average incubation period of 10 to 16 days, they become mildly ill with a ?cold? or may have severe respiratory disease. The extremes of the incubation period are seven days to four weeks, and the duration of the primary disease is from a few days to several weeks. The incubation period and duration and severity of symptoms are usually a function of the magnitude of the exposure. Inhalation of a few conidia is associated with an illness of short duration, where as inhalation of substantial numbers of arthroconidia can lead to acute respiratory failure. Sometimes no respiratory disease is noted. Patients have in varying degrees, one or more of the following symptoms and signs: fever, pain, respiratory embarrassment, cough, and anorexia. Other symptoms are present in varying degrees. Generalized aching, malaise, myalgia, and backaches are often present. In mild cases malaise and lassitude may be the only complaints. Headache may be quite severe in acute, uncomplicated disease. It may subside in a week or persist for a much longer period of time (Rippon, 1988).


            • Symptoms Shown in the Syndrome:

            • Fever (Rippon, 1988):
              • Ontology: UMLS:xxx
              • Description: Most patients are febrile for some period during their illness. There is nothing characteristic about its pattern. The fever usually rises to a peak with diurnal variation and then diminishes. It may last a few hours to a few months; may reach 40.5C, and can be accompanied by night sweats. Persistence or recrudescence of fever following initial recovery often heralds dissemination. Spread of disease may occur in the absence of and without increase of fever, however (Rippon, 1988).
              • Observed: 76%. A report from an epidemic of coccidioidomycosis in the San Joaquin Valley of California between 1991 and 1994 described the present symptoms in 536 patients with new infections. Systemic symptoms included fever (76%), fatigue (39%), and chills (29%) (Feldman and Snyder, 2001).
            • Pain (Rippon, 1988):
              • Ontology: UMLS:xxx
              • Description: Chest pain is very common and is usually the first sign of the disease. It occurs in 70 to 90 per cent of symptomatic patients. Although it may manifest only as a dull discomfiture, pleuritic pain may be so severe and sudden in onset as to emulate rib fracture, myocardial infarction, or cholecystitis. Pain is often accompanied by friction rub and, sometimes, demonstrable pleural fluid levels. Interference with respiration often occurs as the pleuritic pain is made worse by coughing or deep inspiration. Interference with swallowing may result from substernal pain caused by enlargement of the mediastinal nodes (Rippon, 1988). Cavities are frequently asymptomatic, but may produce cough, chest pain, and hemoptysis (Chiller et al., 2003).
              • Observed: 70-90% of symptomatic patients (Rippon, 1988) 44%. A report from an epidemic of coccidioidomycosis in the San Joaquin Valley of California between 1991 and 1994 described the present symptoms in 536 patients with new infections. The clinical symptoms of primary coccidioidomycosis were cough (73%), chest pain (44%), and shortness of breath (32%) (Feldman and Snyder, 2001).
            • Respiratory embarassment (Rippon, 1988):
              • Ontology: UMLS:xxx
              • Description: This symptom is uncommon but may result from the presence of pleural effusion or pneumonic spread of the disease. Although quite rare, shortness of breath may also be due to spontaneous pneumothorax (Rippon, 1988).
              • Observed: 32%. A report from an epidemic of coccidioidomycosis in the San Joaquin Valley of California between 1991 and 1994 described the present symptoms in 536 patients with new infections. The clinical symptoms of primary coccidioidomycosis were cough (73%), chest pain (44%), and shortness of breath (32%) (Feldman and Snyder, 2001). Uncommon among symptomatic patients (Rippon, 1988)
            • Cough (Rippon, 1988):
              • Ontology: UMLS:xxx
              • Description: Cough is less common and less severe in coccidioidomycosis than in other pulmonary infections. It is often nonproductive, but with severe pulmonary involvement sputum may be white or purulent and sometimes blood-streaked (Rippon, 1988). Cavities are frequently asymptomatic, but may produce cough, chest pain, and hemoptysis (Chiller et al., 2003).
              • Observed: Less common among symptomatic patients (Rippon, 1988) 73%. A report from an epidemic of coccidioidomycosis in the San Joaquin Valley of California between 1991 and 1994 described the present symptoms in 536 patients with new infections. The clinical symptoms of primary coccidioidomycosis were cough (73%), chest pain (44%), and shortness of breath (32%) (Feldman and Snyder, 2001).
            • Anorexia (Rippon, 1988):
              • Ontology: UMLS:xxx
              • Description: Anorexia frequently occurs even in mild disease. The duration is usually short, but some patients lose 20 to 30 pounds within a three-week period. In disseminated disease, anorexia may persist and lead to profound cachexia (Rippon, 1988).
              • Observed: Frequent among symptomatic patients (Rippon, 1988)
            • Pulmonary nodule (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: Approximately 5% of patients who develop pneumonia during the primary infection then develop pulmonary nodules. They are usually solitary and patients are mostly asymptomatic. If the nodules do not progress, they pose no serious further problems (Chiller et al., 2003). Approximately 5% to 7% of cases of Coccidioidal pneumonia, whether symptomatic or not, will evolve to form a sharply circumscribed, usually noncalcified, pulmonary nodule (Feldman and Snyder, 2001).
              • Observed: 5% of those who develop pneumonia (Chiller et al., 2003)
            • Pulmonary cavity (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: Cavities also develop in approximately 5% of patients after the acute pneumonia. They are typically solitary, near the pleura, and thin-walled. Patients are generally asymptomatic and approximately half regress after 2 years. Cavities are frequently asymptomatic, but may produce cough, chest pain, and hemoptysis. Occasionally a mycetoma or fungus ball may develop inside the cavity. Infrequently, peripheral cavitary lesions may rupture into the pleural space (Chiller et al., 2003). Another common manifestation of persistent pulmonary coccidioidomycosis is cavity formation, which occurs in about 5% of patients. The typical Coccidioidal cavity is thin walled, solitary, and peripheral in location. They can have fluctuating air-fluid levels or a surrounding parenchymal infiltrate. Coccidioidal cavities are commonly asymptomatic and about 50% will disappear within 2 years of their occurrence. However, it is possible for cavities to persist for years with little change (Feldman and Snyder, 2001).
              • Observed: 5% of those with pnuemonia (Chiller et al., 2003). Another common manifestation of persistent pulmonary coccidioidomycosis is cavity formation, which occurs in about 5% of patients (Feldman and Snyder, 2001).
            • Fungus ball (Chiller et al., 2003):
              • Ontology: UMLS:xxx
            • Ruptured peripheral cavitary lesions (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: Infrequently, peripheral cavitary lesions may rupture into the pleural space (Chiller et al., 2003).
              • Observed: Infrequently among patients with pulmonary cavities (Chiller et al., 2003)
            • Fatigue ():
              • Ontology: UMLS:xxx
              • Observed: 39%. A report from an epidemic of coccidioidomycosis in the San Joaquin Valley of California between 1991 and 1994 described the present symptoms in 536 patients with new infections. Systemic symptoms included fever (76%), fatigue (39%), and chills (29%) (Feldman and Snyder, 2001).
            • Chills ():
              • Ontology: UMLS:xxx
              • Observed: 29% -- A report from an epidemic of coccidioidomycosis in the San Joaquin Valley of California between 1991 and 1994 described the present symptoms in 536 patients with new infections. Systemic symptoms included fever (76%), fatigue (39%), and chills (29%) (Feldman and Snyder, 2001).
            • Generalized aching (Rippon, 1988):
              • Ontology: UMLS:xxx
            • Malaise (Rippon, 1988):
              • Ontology: UMLS:xxx
            • Myalgia (Rippon, 1988):
              • Ontology: UMLS:xxx
            • Backaches (Rippon, 1988):
              • Ontology: UMLS:xxx
            • Headaches (Rippon, 1988):
              • Ontology: UMLS:xxx
              • Description: Headache may be quite severe in acute, uncomplicated disease. It may subside in a week or persist for a much longer period of time (Rippon, 1988).
          • Syndrome -- Primary Cutaneous Disease:
            • Description: This is the rarest form of infection, and it has been adequately documented only in about three cases. The first case was reported in 1927 and involved inoculation of conidia by a prick of a cactus needle, as described by Guy and Jacob. Introduction of spherules into the abraded skin of his finger by a mortician embalming a patient who had died of the disease was the second. The third case involved a laboratory accident in which a graduate student introduced conidia into her thumb. In all three cases a chancrelike lesion developed, there was regional adenitis, and the lesions healed uneventfully within a few weeks (Rippon, 1988).
            • Observed: Only 3 documented cases (Rippon, 1988)


            • Symptoms Shown in the Syndrome:

            • Lesion (Rippon, 1988):
              • Ontology: UMLS:xxx
            • Regional adenitis (Rippon, 1988):
              • Ontology: UMLS:xxx
          • Syndrome -- Allergic Manifestations:
            • Description: Toxic erythema, erythema nodosum, and erythema multiforme are common cutaneous symptoms of early primary coccidioidomycosis. They may occur in the absence of the other clinical signs. The appearance of toxic erythema has no prognostic significance, but development of erythema nodosum or multiforme usually heralds development of strong resistance to the infection. Toxic Erythema frequently appears within in a week of the infection (before coccidioidin skin test sensitivity) and disappears rapidly. There is a fine, macular, diffuse, erythematous rash involving both extremities and the trunk and may include an oral exanthema. It is most common in children and young adults but is found in 10% of older adults. The origin of the erythema is unknown. Though toxic erythemas are found in many acute febrile illnesses, in the endemic areas they are almost pathognomonic for coccidioidomycosis. In about 5 to 10% of cases some other form of allergic manifestation occurs. An erythema nodosum or multiforme-like toxic eruption is found in 25% of adult white females and 4% of white males. It is much less common in dark pigmented people. Other manifestations include arthralgias, arthritis (?desert rheumatism?), and episcleritis. These, along with erythema nodosum (?desert bumps?) and erythema multiforme (?valley fever?), constitute the common benign but symptomatic primary coccidioidomycosis of the highly endemic regions. Other less common allergic phenomena involve the eye. These include episcleritis, phlyctenular conjunctivitis, and keratitis, all of which resolve usually within a few days. When they occur they are often overshadowed by the more spectacular skin rashes and joint pains that may be present in the same patients (Rippon, 1988).


            • Symptoms Shown in the Syndrome:

            • Desert rheumatism (Rippon, 1988):
              • Ontology: UMLS:xxx
              • Description: ?Desert rheumatism? is the name for the arthritis that sometimes accompanies primary disease. The symptoms vary from vague arthralgias to periarticular swelling, stiffness, erythema, and heat. Joint effusion is not found (Rippon, 1988).
            • Erythema nodosum (Rippon, 1988):
              • Ontology: UMLS:xxx
              • Description: The lesions of erythema nodosum are most often restricted to the lower extremities. Usually they are found on the anterior tibial areas, are more numerous about the knees, and may extend to the thighs. Typically they appear as a crop of bright red, tender, itching, or painful raised nodules. They are firm and elastic and deeply imbedded in the skin. They range in size from a few millimeters to several centimeters. The acute lesions regress within a few days. Although the color is initially red to purple, after resolution, the areas may show some degree of brownish post inflammatory hyperpigmentation, which lasts for several weeks or months (Rippon, 1988)
            • Erythema multiforme (Rippon, 1988):
              • Ontology: UMLS:xxx
              • Description: The erythema multiforme-like toxic eruption develops on the upper half of the body. The favored sites are the neck, face, collar, upper back, thorax, and occasionally the arms. They appear as reddish to purple nodules, papules, macules, or vesicles and fade in time to a violaceous or brownish hue. Sometimes they are accompanied by erythema nodosum on the legs. One crop of lesions is the usual pattern, but several crops may appear. Reappearance of such lesions often follows fatigue from physical exertion (Rippon, 1988).
          • Syndrome -- Diffuse pneumonia:
            • Description: Coccidioidomycosis can diffusely involve the lungs in both primary and late disease. In primary infection, diffuse pulmonary involvement can represent multiple sites of infection. This is most often caused by inhalation of large amounts of arthroconidia rather than immunosuppression. Diffuse pneumonia can also represent the result of hematogenous spread of the fungus. This is a rapidly progressive pulmonary disease that may result in respiratory failure and is particularly seen in immunocompromised hosts. On chest radiography this appears as a diffuse reticulonodular pattern throughout the lung. Rarely, C. immitis produces a chronic form of diffuse pneumonia. This is a slowly progressive fibrocavitary process. Patients may have years of pulmonary symptoms plus weight loss and fever (Chiller et al., 2003).


            • Symptoms Shown in the Syndrome:

            • Respiratory failure (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: Diffuse pneumonia can also represent the result of hematogenous spread of the fungus. This is a rapidly progressive pulmonary disease that may result in respiratory failure and is particularly seen in immunocompromised hosts (Chiller et al., 2003).
            • Weight Loss (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: Rarely, C. immitis produces a chronic form of diffuse pneumonia. This is a slowly progressive fibrocavitary process. Patients may have years of pulmonary symptoms plus weight loss and fever (Chiller et al., 2003).
            • Fever (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: Rarely, C. immitis produces a chronic form of diffuse pneumonia. This is a slowly progressive fibrocavitary process. Patients may have years of pulmonary symptoms plus weight loss and fever (Chiller et al., 2003).
          • Syndrome -- Dissemination to the Skin:
            • Description: The skin is the most common site of disseminated disease. There are a variety of skin manifestations; most often these are papules and verrucous lesions. Plaques, superficial abscesses, pustules, and granulomatous lesions can also be seen. Symptoms are usually minor with minimal evidence of acute inflammation. The presence of an ulcerating lesion should make the physician consider the possibility of a sinus tract (Chiller et al., 2003).
            • Observed: Commonly when dissemination occurs (Chiller et al., 2003)


            • Symptoms Shown in the Syndrome:

            • Papules (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: There are a variety of skin manifestations; most often these are papules and verrucous lesions. Plaques, superficial abscesses, pustules, and granulomatous lesions can also be seen (Chiller et al., 2003).
            • Verrucous lesions (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: There are a variety of skin manifestations; most often these are papules and verrucous lesions. Plaques, superficial abscesses, pustules, and granulomatous lesions can also be seen (Chiller et al., 2003).
            • Plaques (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: There are a variety of skin manifestations; most often these are papules and verrucous lesions. Plaques, superficial abscesses, pustules, and granulomatous lesions can also be seen (Chiller et al., 2003).
            • Superficial abscesses (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: There are a variety of skin manifestations; most often these are papules and verrucous lesions. Plaques, superficial abscesses, pustules, and granulomatous lesions can also be seen (Chiller et al., 2003).
            • Pustules (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: There are a variety of skin manifestations; most often these are papules and verrucous lesions. Plaques, superficial abscesses, pustules, and granulomatous lesions can also be seen (Chiller et al., 2003).
            • Granulomatous Lesions (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: There are a variety of skin manifestations; most often these are papules and verrucous lesions. Plaques, superficial abscesses, pustules, and granulomatous lesions can also be seen (Chiller et al., 2003).
          • Syndrome -- Osteomyelitis:
            • Description: Osteomyelitis is also a common manifestation of disseminated disease. The vertebral column is one of the most common sites: other sites are the tibia, skull, metacarpals, metatarsals, femur, and the ribs (Chiller et al., 2003). The most common sites of skeletal involvement in this series were the knee/proximal tibia (6/13 = 46%), spine (4/13 = 31%), and pelvis (2/13 = 15%) (Holley et al., 2002).
            • Observed: 50% of those with disseminated disease (Holley et al., 2002)


            • Symptoms Shown in the Syndrome:

            • Sinus tract (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: In vertebral disease, paraspinal masses with sinus tract formation are common, but vertebral disks are usually unaffected. All sites may develop into ?cold? lesions and manifest abscesses and sinus tracts (Chiller et al., 2003).
            • Cold Lesions (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: In vertebral disease, paraspinal masses with sinus tract formation are common, but vertebral disks are usually unaffected. All sites may develop into ?cold? lesions and manifest abscesses and sinus tracts (Chiller et al., 2003).
            • Abcesses (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: In vertebral disease, paraspinal masses with sinus tract formation are common, but vertebral disks are usually unaffected. All sites may develop into ?cold? lesions and manifest abscesses and sinus tracts (Chiller et al., 2003).
          • Syndrome -- Disemmination to the joints:
            • Description: Infection of the synovium accounts for approximately 20% of patients with hematogenous dissemination. The knee is the most common joints and may present with an isolated synovitis without bony involvement. A single joint is involved in 90% of cases. All joints have been found to be affected, with lower extremities being more common than the upper extremities (Chiller et al., 2003).
            • Observed: 20% of patients with hematogenous dissemination (Chiller et al., 2003)
          • Syndrome -- Meningitis:
            • Description: The spread of C. immitis to the central nervous system is the most lethal form of the infection. This occurs in approximately 200 patients per year in the United States. The most common form presents as chronic granulomatous meningitis, usually involving the basilar meninges. Cerebral and cerebellar abscesses may also be found. The most common symptoms are headache, nausea, vomiting, and altered mental status. Other symptoms and signs have included nuchal rigidity, diplopia, and other cranial neuropathies. Onset of symptoms is usually subacute, but may occur during the primary illness (Chiller et al., 2003).
            • Observed: 200 cases per year in US (Chiller et al., 2003)


            • Symptoms Shown in the Syndrome:

            • Headache (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: The most common symptoms are headache, nausea, vomiting, and altered mental status (Chiller et al., 2003). Although headache is reported as a symptom by approximately 20% of patients with self-limited (nonmeningeal) coccidioidomycosis, physicians should have a low threshold to examine the cerebrospinal fluid (CSF) of patient whose headache is severe, persists, or is associated with other findings referable to the central nervous system (Chiller et al., 2003).
              • Observed: 20% among nonmeningeal infections
            • Nausea (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: The most common symptoms are headache, nausea, vomiting, and altered mental status (Chiller et al., 2003).
            • Vomiting (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: The most common symptoms are headache, nausea, vomiting, and altered mental status (Chiller et al., 2003).
            • Altered mental status (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: The most common symptoms are headache, nausea, vomiting, and altered mental status (Chiller et al., 2003).
            • Nuchal rigidity (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: Other symptoms and signs have included nuchal rigidity, diplopia, and other cranial neuropathies (Chiller et al., 2003)
            • Diplopia (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: Other symptoms and signs have included nuchal rigidity, diplopia, and other cranial neuropathies (Chiller et al., 2003).
            • Cranial neuropathies (Chiller et al., 2003):
              • Ontology: UMLS:xxx
              • Description: Other symptoms and signs have included nuchal rigidity, diplopia, and other cranial neuropathies (Chiller et al., 2003).
          • Syndrome -- Dissemination to other sites:
            • Description: Coccidioidomycosis has been found in almost every organ. Reports of infection involving the eye, larynx, thyroid, and peritoneum have been reviewed in the literature. There are also cases of genitourinary disease of the prostate, kidney, and uterus. Infections involving prosthetic grafts and peritoneal shunts have also been reported (Chiller et al., 2003).
          • Syndrome -- Hyphal growth associated with plastic devices:
            • Description: The hyphal or soil form is found rarely in human tissue. We report 5 cases of coccidioidomycosis in which hyphae were found in brain tissue or spinal fluid. The presence of central nervous system plastic devices appears to be associated with morphological reversion to the saprophytic form. This reversion has implications for diagnosis and therapy and may increase the risk of obstruction of the device(s) (Hagman et al., 2000).
            • Observed: Rare (Hagman et al., 2000)

        6. Treatment Information:
          • Amphotericin B deoxycholate (AmB): Amphotericin B (AmB) has been available for over 40 years and remains the treatment of choice for invasive fungal infections, yet its use is limited by drug related toxicity ? particularly nephrotoxicity. As a result, the high doses required to treat severe invasive fungal infections often cannot be achieved (Martino, 2004) Amphotericin B deoxycholate (AmB) is usually reserved for severe infections, where disease is rapidly progressing. Doses given in the range of 0.5 mg/kg to 0.7 mg/kg intravenously are used (Chiller et al., 2003).
            • Contraindicator:
            • Complication: Nephrotoxicity is the most common serious side effect of Am B therapy. It occurs early in the course of treatment, generally within the first 2 weeks, and usually is reversible. Tubular damage and a decreased glomerular filtration rate manifest themselves by impaired concentrating ability, sodium / potassium wasting, tubular acidosis, and azotemia. The nephrotoxicity of Am B is potentiated by sodium depletion (diuretics, poor oral intake, or vomiting) and by interactions with other nephrotoxic drugs (cyclosporine A, aminoglycosides, pentamidine, digitalis). Mild-to-moderate increases in creatinine are very common in children receiving Am B and should not prompt discontinuation of the drug. To reduce the likelihood of renal toxicity, careful and frequent monitoring of electrolytes (sodium, potassium, magnesium) and kidney function are key. Am B dosage usually is adjusted when a child?s BUN/creatinine level reaches three times pretreatment levels. The drug is discontinued first for 24 hours, then resumed at half the previous dose and gradually titrated upward as permitted by the BUN and creatinine levels. Among the most common adverse effects associated with Am B therapy are fever, chills, rigors, and nausea, probably mediated by tumor necrosis factor and prostaglandins. Decreasing the rate of infusion, premedicating patients with nonsteriodal anti-inflammatory drugs and diphenhydramine and, in more severe cases, with hydrocortisone and/or meperidine, can reduce the frequency of these effects significantly. Thrombophlebitis at the site of peripheral intravenous line also is a frequent occurrence, an d it usually is ameliorated by adding 1000 units of heparin to the infusion. A normocytic/normochromic anemia, probably from suppression of erythropoietin or direct marrow toxicity, is another frequent treatment complication; it reverses following withdrawal of the drug (Abadi et al., 1995).
            • Drug Resistance: Resistance to amphotericin B is quite rare and it is often caused by a decrease in either the amount of ergosterol in the plasmalemma or a change in the target lipid, which leads to a decrease in the binding of amphotericin B (MIC > 2 mg/L). Overall, the development of resistance to amphotericin B has not been a significant factor in the treatment of patients (Ellis, 2002).
          • Amphotericin B - Lipid Complex (ABLC): Amphotericin B - Lipid Complex (ABLC) at a dose of 5 mg/kg/day appears to be safe and effective for the treatment of proven or suspected systemic fungal infections in adults and children who are refractory or intolerant to conventional AmB. ABLC is effective against a wide range of pathogens, including invasive candidiasis, invasive aspergillosis, cryptococcal meningitis and disseminated cryptococcosis in HIV-infected patients, fusariosis, coccidioidomycosis, zygomycosis and blastomycosis. ABLC has superior efficacy to conventional AmB (reducing risk of mortality by 28%, NNT = 31) and superior tolerability to conventional AmB (reducing risk of nephrotoxicity by 58%, NNT = 6). This good efficacy and tolerability, together with the low cost of ABLC, mean that it is possibly the most cost-effective antifungal agent available (Martino, 2004).
            • Contraindicator:
            • Complication: Amphotericin B - Lipid Complex (ABLC) has superior tolerability to conventional AmB (reducing risk of nephrotoxicity by 58%, NNT = 6) (Martino, 2004).
            • Success Rate: 40% - 86% (Median 63%) for treatment of documented fungal infections (Martino, 2004)
            • Drug Resistance: Resistance to amphotericin B is quite rare and it is often caused by a decrease in either the amount of ergosterol in the plasmalemma or a change in the target lipid, which leads to a decrease in the binding of amphotericin B (MIC > 2 mg/L). Overall, the development of resistance to amphotericin B has not been a significant factor in the treatment of patients (Ellis, 2002).
          • Fluconazole: Fluconazole is probably the most frequently used medicine given its tolerability, although high relapse rates have been reported in some studies. Usually doses of 400 mg/d are given, but it has been used in doses as high as 100 mg/d without complications (Chiller et al., 2003).
            • Complication: Adverse events that could have been caused by the study drug were vomiting. Patients were withdrawn from the study because of mild to moderate symptoms, such as rash, dry skin, or nausea. The relationship of these events to the study drug is uncertain. Of interest, alopecia was reported in 15 of 97 patients receiving fluconazole (15%) and only 4 of 101 patients receiving itraconazole (4%) (P=0.01). This confirms previous reports that suggest an association between fluconazole and hair loss. Similarly, dry lips were reported in 11 of 97 patients receiving fluconazole (11%) and in 0 of 101 patients receiving itraconazole (P=0.008). Dry skin and cheilitis have previously been reported with fluconazole therapy (Galgiani et al., 2000).
            • Success Rate: 50%: Overall, 47 of 94 patients (50%) responded to fluconazole. In patients with skeletal infections, the proportion of responders in the fluconazole group was 7 of 27 patients (26%) at 8 months, and 54 of 94 (57%) at 12 months (Galgiani et al., 2000).
          • Itraconazole: Itraconazole in both capsules and solution has also been shown to be effective. Doses range from 400 to 600 mg/d. Relapse rates may be lower than with fluconazole. A recent study comparing fluconazole with itraconazole in the treatment of nonmeningeal coccidioidomycosis showed a trend toward better efficacy with itraconazole in skeletal forms of disseminated infection but did not show significant differences between the two drugs after 8 months, the planned duration of observation. The advantage of itraconazole, however, became statistically demonstrable 12 months after therapy started (Chiller et al., 2003).
            • Complication: Adverse events that could have been caused by the study drug were: elevated liver enzyme levels and hypokalemia. Two deaths in itraconazole-treated patients (2%) were attributed to underlying disease (sepsis associated with chemotherapy-induced neutropenia and cardiac arrest). Patients were withdrawn from the study because of mild to moderate symptoms and difficulty concentrating. The relationship of these events to the study drug is uncertain. Of interest, alopecia was reported in 15 of 97 patients receiving fluconazole (15%) and only 4 of 101 patients receiving itraconazole (4%) (P=0.01). This confirms previous reports that suggest an association between fluconazole and hair loss. Similarly, dry lips were reported in 11 of 97 patients receiving fluconazole (11%) and in 0 of 101 patients receiving itraconazole (P=0.008). Dry skin and cheilitis have previously been reported with fluconazole therapy (Galgiani et al., 2000).
            • Success Rate: 63%: Overall, 47 of 94 patients (50%) responded to fluconazole and 61 of 97 patients (63%) responded to itraconazole, a difference of 13 percentage points (95% CI, 22 to 28 percentage points; P 5 0.08) that did not allow us to reject the null hypothesis. All three of the subgroups classified by primary site of infection showed a trend for superiority of itraconazole. This trend was most striking in patients with skeletal infections: At 8 months, the proportion of responders in the itraconazole group (12 of 23 patients [52%]) was two times greater than that in the fluconazole group (7 of 27 patients [26%]) (Galgiani et al., 2000).
          • Ketoconazole: The oral azoles offer a useful alternative treatment of meningeal disease. Ketoconazole at doses of 800 to 1200 mg per day, which are considerably higher than the doses for nonmeningeal disease, can produce responses, but side effects at these high doses, including gastrointestinal problems and steroid blockade, make this drug the least desirable choice (Stevens, 1995).
            • Voriconazole: Voriconazole (VRC) is a novel triazole antifungal, recently approved in Europe for treatment of serious infections caused by Aspergillus, Fusarium, Scedosporium, and resistant Candida species. Voriconazole has demonstrated comparable, or better, in vitro activity than Itraconzole (ITC) and Amphotericin B (AMB) against Aspergillus (mean MICs 0.19-0.58 ?g/ml), Ascomycetes, Bipolaris, Fusarium, Blastomyces dermatitidis, Coccidioides immitis, dermatophytes, Histoplasma capsulatum, Malassezia, and Scedosporium angiospermum (P. boydii) (Ghannoum and Kuhn, 2002).
              • Contraindicator: These drugs are contraindicated with treatment including Voriconazole: Astemizole, Barbiturates (long acting), Carbamazepine, Cisapride, Pimozide, Quinidine, Rifampin, Sirolimus, Terfenadine. Finally, azoles have been shown to be teratogenic in animal studies. In rats, high doses of VRC (60 mg/kg/day) gave class-related teratogenicity, and there may be effects at lower dose levels. Until more information is available, when given VRC, women of childbearing potential should use contraception; pregnant women should only be administered the drug if the benefits clearly outweigh the risks (Ghannoum and Kuhn, 2002).
              • Complication: Voriconazole (VRC) is safe and well tolerated; the most common side effect is benign, self-limited visual disturbance (Ghannoum and Kuhn, 2002)
            • Surgery: Pulmonary resection has a role in managing severe hemoptysis or cavities that rupture or enlarge during chemotherapy. Surgery is also indicated to drain empyemas, close persistent bronchopleural fistulas, or expand lungs that are restricted by residual disease. Other indications for surgery are controversial. The risk of ongoing pulmonary disease after subsequent medical treatment must be weighed against the risks of complications and recurrent disease, which are common after resection. In patients with musculoskeletal disease, resection of sequestra and drainage of adjacent areas of purulent soft tissue may be indicated. Immobilization of an infected limb is also useful. Synovectomy, arthrodesis, or in rare cases, amputation of an infected structure may be required (Stevens, 1995).
              • Contraindicator: The risk of ongoing pulmonary disease after subsequent medical treatment must be weighed against the risks of complications and recurrent disease, which are common after resection (Stevens, 1995).
            • Categories and Strengths of Treatment Recommendations for the Management of Specific Clinical Entities caused by C. immitis: Each recommendation is followed by a parenthetical reference to the category and grade of disease. The category (A-E; A - Good evidence for use, B - Moderate evidence for use, C. - Poor evidence for or against use, D - Moderate evidence against use, and E - Good evidence against use) indicates the strength of each recommendation for or against use, and the grade (I, II, or III; I - from at least 1 properly randomized, controlled trial, II - Evidence from at least 1 well-designed study without randomization, III - Evidence from expert opinions of respected authorities) indicates the quality of evidence on which the recommendation is based (Galgiani et al., 2000).
              • Uncomplicated Primary Respiratory Infection: Management of primary respiratory infections due to C. immitis is very controversial because of the lack of prospective, controlled trails. For many, if not most, patients, management may rely on periodic reassessment of symptoms and radiographic findings to assure resolution without antifungal treatment. On the other hand, some authorities propose treatment of all symptomatic patients (CIII). Concurrent risk factors (i.e., HIV infection, organ transplant, or high doses of corticosteroids) or evidence of unusually severe infections should lead to the initiation of antifungal therapy (AII). Diagnosis of primary infection during the third trimester of pregnancy or immediately in the postpartum period should raise consideration for treatment (AIII). During pregnancy, amphotericin B is the treatment of choice because fluconazole and likely other azole antifungals are teratogenic (AIII). Although opinion varies on the most relevant factors to judge severity, commonly used indicators are weight loss of >10%, intense night sweats persisting for 13 weeks, infiltrates involving more than one-half of 1 lung or portions of both lungs, prominent or persistent hilar adenopathy, concentrations of CF antibody to C. immitis of 11 : 16, as determined by a reference method or an equivalent titer, failure to develop dermal hypersensitivity to coccidioidal antigens, inability to work, or symptoms that persist for 12 months. Persons of African or Filipino descent have a higher risk for dissemination, and this fact may also be taken into consideration (BIII). Commonly prescribed therapies include currently available oral azole antifungals at their recommended doses. Courses of typically recommended treatment range from 3 to 6 months (Galgiani et al., 2000).
                • Contraindicator: Diagnosis of primary infection during the third trimester of pregnancy or immediately in the postpartum period should raise consideration for treatment (AIII). During pregnancy, amphotericin B is the treatment of choice because fluconazole and likely other azole antifungals are teratogenic (AIII) (Galgiani et al., 2000).
              • Diffuse pneumonia: When bilateral reticulonodular or miliary infiltrates are produced by C. immitis, there is probably an underlying immunodeficiency state. Therapy usually starts with amphotericin B (AIII). Several weeks of therapy are often required to produce clear evidence of improvement. After this time during convalescence, amphotericin B treatment may be discontinued and replaced with oral azole antifungal therapy (BIII). In combination, the total length of therapy should be at least 1 year, and for patients with severe immunodeficiency, oral azole therapy should be continued as secondary prophylaxis (AIII) (Galgiani et al., 2000).
                • Complication: Because diffuse pneumonia due to C. immitis is usually a manifestation of fungemia, patients should be evaluated for other extrapulmonary lesions that may also require attention (Galgiani et al., 2000).
              • Asymptomatic Pulmonary Nodule: If a solitary nodule is determined to be due to C. immitis by noninvasive means or by fine-needle aspiration, specific antifungal therapy or resection is unnecessary (EIII). Similarly, in the absence of significant immunosuppression, antifungal therapy is not recommended if the lesion is completely resected and the diagnosis is determined from examination of the excised tissue (Galgiani et al., 2000).
                • Contraindicator: Similarly, in the absence of significant immunosuppression, antifungal therapy is not recommended if the lesion is completely resected and the diagnosis is determined from examination of the excised tissue (Galgiani et al., 2000).
              • Asymptomatic Pulmonary Cavity: Many cavities due to C. immitis are benign in their course and do not require intervention. Such cavities harbor viable fungus, and cultures of sputum or other respiratory secretions commonly yield colonies of C. immitis. Most authorities do not consider these characteristics of asymptomatic cavities sufficient reason to initiate treatment. Moreover, in the absence of controlled clinical trials, we lack evidence that antifungal therapy has a salutary effect on the course of asymptomatic coccidioidal cavities (BIII). With the passage of time, some cavities disappear, obviating the need for intervention. Although indefinite follow-up without intervention is appropriate for many patients, eventual resection from 1 to several years after the cavity is identified may be recommended to avoid future complications, especially if the cavity is still detectable after 2 years, if it demonstrates progressive enlargement, or if it is immediately adjacent to the pleura (BIII) (Galgiani et al., 2000).
                • Symptomatic Pulmonary Cavity: Should these complications occur, oral therapy with azole antifungals may result in improvement, although recurrence of symptoms, at least in some patients, occurs upon cessation of therapy. Where the surgical risks are not unusually high, resection of localized cavities will probably resolve the problem and may be recommended as an alternative approach to chronic or intermittent therapy (Galgiani et al., 2000).
                  • Complication: Complications of coccidioidal cavities are local discomfort, superinfection with other fungi or possibly bacteria, or hemoptysis (Galgiani et al., 2000).
                • Ruptured Pulmonary Cavity: For young, otherwise healthy patients, surgical closure by lobectomy with decortication is the preferred management (AII). Antifungal therapy is recommended for coverage, particularly in acute cases with active disease, delay of diagnosis, or coexistent diseases (CIII). For patients for whom the diagnosis was delayed >1 week or in whom there are coexistent diseases, management approaches are less uniform and may include courses of therapy with amphotericin B or oral azole antifungals before surgery, or chest tube drainage without surgery (CIII) (Galgiani et al., 2000).
                  • Complication: Rupture of a coccidioidal cavity into the pleural space that results in pyopneumothorax is an infrequent but well-recognized complication (Galgiani et al., 2000).
                • Chronic Fibrocavitary Pneumonia: Initial treatment of chronic fibrocavitary pneumonia is with oral azole antifungals (AII). If the patient?s condition improves sufficiently, therapy should be continued for at least 1 year. If therapy is not satisfactory, alternatives are switching to an alternative azole antifungal, raising the dose of fluconazole if it was the oral azole initially selected, and administering therapy with amphotericin B (BIII). Surgical resection may be a useful option for refractory lesions that are well localized or where significant hemoptysis has occurred (Galgiani et al., 2000).
                  • Nonmeningeal Disseminated Infection: Therapy is usually initiated with oral azole antifungals (AII). Clinical trials have used 400 mg/d of ketoconazole, itraconazole, or fluconazole. Some experts recommend higher dosages of fluconazole (BIII). Amphotericin B is alternative therapy, especially if lesions are appearing to worsen rapidly and are in particularly critical locations such as the vertebral column (BIII). The dosage of amphotericin B is similar to that for treatment of diffuse coccidioidal pneumonia, although the duration may be longer. Surgical debridement or stabilization is an occasionally important if not critical adjunctive measure (Galgiani et al., 2000)
                    • Meningitis: Therapy with oral fluconazole is currently preferred. The dosage used in reported clinical trials was 400 mg/d (AII). Some physicians begin therapy with 800 or 1000 mg/d of fluconazole (BIII). Dosages of itraconazole of 400?600 mg/d have also been reported to be comparably effective (BII). Some physicians initiate therapy with intrathecal amphotericin B in addition to an azole on the basis of their belief that responses are more prompt with this approach. The dose and duration of intrathecal amphotericin B in this circumstance have not been defined (CIII). Patients who respond to azole therapy should continue this treatment indefinitely (AIII). Hydrocephalus nearly always requires a shunt for decompression (AIII). Hydrocephalus may develop regardless of the therapy being used, and switching to alternative therapy is not required (BIII). Patients who do not respond to fluconazole or itraconazole treatment are candidates for intrathecal amphotericin B therapy with or without continuation of azole treatment. The intrathecal dose of amphotericin B normally ranges from 0.01 to 1.5 mg; it is administered at intervals ranging from daily to weekly, beginning at a low dose and increasing until patient intolerance appears (Galgiani et al., 2000).

    4. Prevention:
      1. Dust abatement (Kirkland and Fierer, 1996):
        • Ontology: UMLS:xxx
        • Description: Simple environmental measures, such as planting grass or paving roads in highly populated areas, decrease the amount of airborne dust and lower the risk for coccidioidomycosis. These measures do not necessarily eradicate C. immitis from the soil but lower the risk for airborne dispersion of the organism. At present, no practical method exists for eliminating C. immitis from the soil (Kirkland and Fierer, 1996).
      2. Soil modification (Galgiani, 1999):
        • Ontology: UMLS:xxx
        • Description: 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, 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 (Galgiani, 1999).
      3. Education (Galgiani, 1999):
        • Ontology: UMLS:xxx
        • Description: 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 (Galgiani, 1999).
      4. Killed Spherule Vaccine (Pappagianis, 1993):
        • Ontology: UMLS:xxx
        • Description: A vaccine consisting of formaldehyde-killed spherules of Coccidioides immitis, previously shown to provide protection against development of lethal coccidioidomycosis in laboratory animals, was evaluated in humans. This double blind "Phase 3" study, conducted during the period 1980 to 1985, involved 2,867 healthy subjects with no history of coccidioidomycosis and negative skin tests. Randomized into vaccine (n = 1,436) or placebo (n = 1,431) groups, the former received three intramuscular injections of 1.75 mg (dry weight) of spherules, the latter received three injections of sterile 0.85% NaCl solution. Compatible clinical presentation with cultural or serologic findings permitted detection of coccidioidomycosis. Of those receiving vaccine, nine developed coccidioidomycosis and nine additional were suspected of having the disease. Of the group receiving placebo, 12 developed coccidioidomycosis, and 13 additional were suspected of having the disease. All cases and suspected cases were mild. Under the conditions of this study, a slight but statistically insignificant reduction in the incidence of coccidioidomycosis was noted in the vaccinated group compared with that in the placebo group, and there was no discernible difference in severity of disease between these groups (Pappagianis, 1993). An uncommon disease in a national context, coccidioidomycosis has substantial ramifications for several regions where epidemics have produced reported annual case rates as high as 15 per 100,000 and substantial economic impact. Diseases affecting <200,000 persons annually (orphan diseases) require more incentives for research and development. Our findings may contribute to the policy decisions for vaccine development and distribution for C. immitis. Our analysis suggests that a vaccine against C. immitis would have substantial public health benefit. An update of this cost-effectiveness analysis can be performed when the results of human vaccine trials become available (Barnato et al., 2001).
        • Efficacy:
          • Rate: < 68%. The numbers of diagnosed cases were sufficient to rule out a prevention rate of 80%. The 95% confidence interval showed an upper limit of 68% for the prevention rate (Pappagianis, 1993).
        • Complication: Injection site tolerability: This dose (1.75mg, about 1/1,000 of the immunizing dose/kg for mice) produced local swelling and marked discomfort in 6.6% of recipients, unacceptable discomfort in 0.6% (Pappagianis, 1993).
      5. :
        • Ontology: UMLS:xxx
        • Description: ()
        • Efficacy:
          • Rate:

    5. Model System:
      1. Mouse (Miyaji, 1987):
        1. Ontology: UMLS:xxx
        2. Model Host: Mammals. The laboratory mouse has been used in numerous studies on C. immitis. These include studies on the immunology, pathology, antifungal therapy, and immunoprophylaxis of coccidioidomycosis (Miyaji, 1987).
        3. Model Pathogens:
          • Coccidioides immitis . Most commonly, the arthroconidia are instilled or inoculated by the desired route of infection. Low doses of arthroconidia (i.e. <50 to 100) often result in chronic infections whereas increased doses (i.e., > 100 to 500) result in rapidly fatal disease. While strains of C. immitis vary in virulence, selection of a suitable strain and careful maintenance of cultural conditions allow for a predictable experimental disease (Miyaji, 1987).
        4. Description: Intranasal (i.n.) instillations of arthroconidia is used most often to produce pulmonary disease. Systemic coccidioidomycosis can be produced in mice by injection of C. immitis either intraperitoneally (i.p.) or intravenously (i.v.) Several studies utilized the i.p. route to study resistance mechanisms and potential vaccines against C. immitis. Intravenous inoculation of C. immitis is less frequently used to establish systemic disease (Miyaji, 1987). The mouse has been used most extensively. Four routes of infection have been used in these murine models. They include intranasal instillation, intraperitoneal, and intravenous inoculation of arthroconidia; and intracerebral injection of endospores. As life-long immunity to C. immitis can develop after infection, many investigators have used murine models to address questions concerning the immunology of host-resistance, such as cytokine expression, and the immunoprophylaxis of the disease (Sorensen et al., 1999).
      2. Macaque:
        1. Ontology: UMLS:xxx
        2. Model Host: Mammals. Several other animals (i.e., dogs, guinea pigs, and monkeys) have been used to study possible vaccines against C. immitis as well as immunologic responses (Miyaji, 1987).
        3. Model Pathogens:
          • Coccidioides immitis . Most commonly, the arthroconidia are instilled or inoculated by the desired route of infection. Low doses of arthroconidia (i.e. <50 to 100) often result in chronic infections whereas increased doses (i.e., > 100 to 500) result in rapidly fatal disease. While strains of C. immitis vary in virulence, selection of a suitable strain and careful maintenance of cultural conditions allow for a predictable experimental disease (Miyaji, 1987).
        4. Description: Levine et al. used cynomologous monkeys to study the effectiveness of a killed spherule vaccine. Their results indicated that approximately 5mg/kg provided protection against an otherwise lethal aerosol of 200 arthroconidia (Miyaji, 1987).
      3. Rhesus Monkey (Website 8):
        1. Ontology: UMLS:xxx
        2. Model Host: Mammals. Several other animals (i.e., dogs, guinea pigs, and monkeys) have been used to study possible vaccines against C. immitis as well as immunologic responses (Miyaji, 1987).
        3. Model Pathogens:
          • Coccidioides immitis . Most commonly, the arthroconidia are instilled or inoculated by the desired route of infection. Low doses of arthroconidia (i.e. <50 to 100) often result in chronic infections whereas increased doses (i.e., > 100 to 500) result in rapidly fatal disease. While strains of C. immitis vary in virulence, selection of a suitable strain and careful maintenance of cultural conditions allow for a predictable experimental disease (Miyaji, 1987).
        4. Description: Lowe et al. examined the serological and skin test responses of Macaca mulatta monkeys after vaccination and aerosol challenge with C. immitis. Their results indicated similarities to human responses with some discrepancies in the tube-preciptin reactions from the monkey?s sera (Miyaji, 1987).
      4. Guinea Pig (Miyaji, 1987):
        1. Ontology: UMLS:xxx
        2. Model Host: Mammals. Several other animals (i.e., dogs, guinea pigs, and monkeys) have been used to study possible vaccines against C. immitis as well as immunologic responses (Miyaji, 1987).
        3. Model Pathogens:
          • Coccidioides immitis . Most commonly, the arthroconidia are instilled or inoculated by the desired route of infection. Low doses of arthroconidia (i.e. <50 to 100) often result in chronic infections whereas increased doses (i.e., > 100 to 500) result in rapidly fatal disease. While strains of C. immitis vary in virulence, selection of a suitable strain and careful maintenance of cultural conditions allow for a predictable experimental disease (Miyaji, 1987).
        4. Description: Cox et al. infected guinea pigs intratracheally with 50 arthroconidia of C. immitis and followed the temporal course of disease culturally and immunologically. They found the overall immunologic response of guinea pigs to infection were consistent with the pattern in humans but with no obvious correlation between dissemination and complement-fixing antibody titers. In addition, extrapulmonary dissemination of C. immitis was found to be an early event in the guinea pigs. Other investigators have demonstrated guinea pigs were susceptible to aerosol infection. Guinea pigs also have been used to study responsiveness to C. immitis antigens with the induction of anergy, skin-test responsiveness, and adoptive transfer of skin-test sensitivity utilizing transfer factor (Miyaji, 1987).
      5. Dog (Miyaji, 1987):
        1. Ontology: UMLS:xxx
        2. Model Host: Mammals. Several other animals (i.e., dogs, guinea pigs, and monkeys) have been used to study possible vaccines against C. immitis as well as immunologic responses (Miyaji, 1987).
        3. Model Pathogens:
          • Coccidioides immitis . Most commonly, the arthroconidia are instilled or inoculated by the desired route of infection. Low doses of arthroconidia (i.e. <50 to 100) often result in chronic infections whereas increased doses (i.e., > 100 to 500) result in rapidly fatal disease. While strains of C. immitis vary in virulence, selection of a suitable strain and careful maintenance of cultural conditions allow for a predictable experimental disease (Miyaji, 1987).
  2. Mammals:
    1. Taxonomy Information:
      1. Species:
        1. Nine-banded armadillo (Website 4):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9361
          • Scientific Name: Dasypus novemcinctus (Website 4)
          • Description: All the captured armadillos seemed to be healthy. No macroscopic abnormalities were observed in macroscopic examination of their excised organs. No fungal elements could be disclosed in the microscopic examination of the teased or cut sectioned and GMS stained tissues. No tissue reactions were observed in the H&E stained cut sections. However, white to cream colored velvety colonies grew up in the cultures of homogenized spleen of three and from the liver of two armadillos. Two of the animals were captured in Paulistana and the remaining one in Passagem Franca. The colonies were formed by hyaline, septate, branched hyphae, in most of which barrel shaped arthroconidia alternating with empty cells, were observed. Mice inoculated with these isolates presented a widespread coccidioidomycosis. Immature and mature spherules of C. immitis were easily disclosed by microscopic examination of the internal organs of the inoculated mice (Eulalio et al., 2001).
        2. Przewalski's horse (Website 5):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9798
          • Scientific Name: Equus przewalskii (Website 5)
          • Description: Przewalski?s horses (Equus przewalskii), once extinct in the wild, have been successfully bred in captivity and returned to Mongolia. In general, few health problems have been noted, aside from trauma, in captive herds. Przewalski?s horses are presumed to be susceptible to infectious diseases of the domestic horse (Equus caballus) and other equids. However, reports of infectious disease are rare possibly because of the lack of exposure to other equids and prophylactic vaccination. Single cases of equine rhinopneumonitis, equine influenza, and two cases of coccidioidomycosis have been reported in captive Przewalski?s horses. Necropsy records and hematoxylin-eosin (H&E)?stained histopathology slides from all Przewalski?s horses (n = 30, 15 males, 15 females) >1 mo of age that died between 1984 and 2000 at the San Diego Wild Animal Park (SDWAP, 15500 San Pasqual Valley Road, Escondido, California 92027, USA) were reviewed. Przewalski?s horses had a high incidence of disseminated coccidioidomycosis that was not present in the other equids housed at SDWAP. The absence of disseminated disease in other equids and location of affected Przewalski?s horses in multiple enclosures, some of which currently or previously housed other exotic equids, suggests that Przewalski?s horses are uniquely susceptible to infection with this saprophytic fungus (Terio et al., 2003).
        3. Horse (Website 11):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9796
          • Scientific Name: Equus caballus (Website 11)
          • Description: The mare had been resident in Chino Valley, a region endemic for coccidioidomycosis. She had been ill for 6 months; despite antibacterial therapy, roentgenographically and bronchoscopically documented mediastinal disease (not associated with cough) persisted, and joint disease developed. Suffering and incurably ill from a disseminated infection (thought to be caused by Corynebacterium pseudo-tuberculosis), 3 days after admission the mare was killed by lethal injection. Abscesses were found in the mediastinal lymph nodes, lungs, kidneys, spleen, and liver by dissection requiring the use of rib cutters, bone saw, scissors, and scalpel. Pus from the abscesses eventually yielded C. immitis in cultures (Kohn et al., 1992).
        4. Dog (Website 10):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9615
          • Scientific Name: Canis familiaris (Website 10)
          • Description: Since the first case of coccidioidomycosis in dogs was described in 1939, the dog has been recognized as one of the most susceptible species. Among all animals, dogs show the most recognizable signs of coccidioidal disease, although acute primary infections often go unnoticed by the owners. Medical records and laboratory data from 218 cases of canine coccidioidomycosis diagnosed at the University of California, Davis, CA, USA were reviewed. The diagnoses were based on clinical signs in conjunction with positive qualitative and quantitative immunodiffusion serological testing, histopathology, and mycology. Forty-three breeds were represented, as well as numerous mixed-breed dogs. Large and medium sized dogs predominated. Coccidioidomycosis occurred frequently in young adult dogs. Males were affected more commonly than females. Clinical signs noted at presentation included fever, lethargy, partial anorexia with associated weight loss, exercise intolerance, cough and lameness. Primary pulmonary infection occurred most commonly. Evidence of extrapulmonary dissemination occurred most commonly to appendicular bone and overlying skin, but also included visceral (hepatic, splenic, renal), pericardial: myocardial, central nervous system, ocular and prostatic involvement. Extrapulmonary dissemination was associated with a poorer prognosis and increased incidence of euthanasia or death (Pier et al., 2000).
        5. Domestic Cat (Website 12):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9685
          • Scientific Name: Felis catus (Website 12)
          • Description: Domestic cats are infected, and dissemination, although rare, occurs more frequently than the single published report would indicate (Pier et al., 2000).
        6. Cow or Domestic Cattle (Website 13):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9913
          • Scientific Name: Bos taurus (Website 13)
          • Description: Lesions found in slaughtered cattle, cheep and swine reflect self-limiting pulmonary disease (Pier et al., 2000)
        7. Sheep (Website 14):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9940
          • Scientific Name: Ovis aries (Website 14)
          • Description: Starting in 1918 with description of coccidioidomycosis lesions in cattle the disease has been found in sheep, swine, horses, burros, domestic cats, dogs, coyotes, desert rodents, a variety of nonhuman primates, many zoo animals, some uncommon pet and companion animals, and a snake (Pier et al., 2000).
        8. Pig or Swine (Website 15):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9823
          • Scientific Name: Sus scrofa (Website 15)
          • Description: Starting in 1918 with description of coccidioidomycosis lesions in cattle the disease has been found in sheep, swine, horses, burros, domestic cats, dogs, coyotes, desert rodents, a variety of nonhuman primates, many zoo animals, some uncommon pet and companion animals, and a snake (Pier et al., 2000).
        9. Ass or Burro (Website 16):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9793
          • Scientific Name: Equus asinus (Website 16)
          • Description: Starting in 1918 with description of coccidioidomycosis lesions in cattle the disease has been found in sheep, swine, horses, burros, domestic cats, dogs, coyotes, desert rodents, a variety of nonhuman primates, many zoo animals, some uncommon pet and companion animals, and a snake (Pier et al., 2000).
        10. Coyote (Website 17):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9614
          • Scientific Name: Canis latrans (Website 17)
          • Description: Starting in 1918 with description of coccidioidomycosis lesions in cattle the disease has been found in sheep, swine, horses, burros, domestic cats, dogs, coyotes, desert rodents, a variety of nonhuman primates, many zoo animals, some uncommon pet and companion animals, and a snake (Pier et al., 2000).
        11. Rodents (Website 18):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9989
          • Scientific Name: Rodentia (Website 18)
          • Description: Starting in 1918 with description of coccidioidomycosis lesions in cattle the disease has been found in sheep, swine, horses, burros, domestic cats, dogs, coyotes, desert rodents, a variety of nonhuman primates, many zoo animals, some uncommon pet and companion animals, and a snake (Pier et al., 2000).
        12. Primates (Website 19):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 9443
          • Scientific Name: Primates (Website 19)
          • Description: Starting in 1918 with description of coccidioidomycosis lesions in cattle the disease has been found in sheep, swine, horses, burros, domestic cats, dogs, coyotes, desert rodents, a variety of nonhuman primates, many zoo animals, some uncommon pet and companion animals, and a snake (Pier et al., 2000).
        13. Snakes (Website 20):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 8570
          • Scientific Name: Serpentes (Website 20)
          • Description: Starting in 1918 with description of coccidioidomycosis lesions in cattle the disease has been found in sheep, swine, horses, burros, domestic cats, dogs, coyotes, desert rodents, a variety of nonhuman primates, many zoo animals, some uncommon pet and companion animals, and a snake (Pier et al., 2000).
        14. Sea Otters (Website 21):
          • Ontology: UMLS:xxx
          • GenBank Taxonomy No.: 34882
          • Scientific Name: Enhydra lutris (Website 21)
          • Description: Disseminated coccidioidomycosis has been diagnosed in six southern sea otters (Enhydra lutris nereis) found dead or dying along the Pacific coast of California. The pathological findings in disseminated coccidioidomycosis in sea otters were similar to those described in other species, but pleuritis was more striking and consistent. The pronounced and uniform involvement of the respiratory system indicates that the likely route of exposure for sea otters was inhalation, as in other species. The uniformity of disseminated lesions suggests that sea otters have a low resistance to the agent. The definitive mechanism for marine mammal exposure to a soil-associated fungus is unknown but likely reflects soil contamination of the water (Pier et al., 2000).

    2. Infection Process:

      No infection process information is currently available here.

    3. Disease Information:

      No disease information is currently available here.

    4. Prevention:

      No prevention information is currently available here.

    5. Model System:

      No model system information is currently available here.


IV. Labwork Information

A. Biosafety Information:
  1. Biosafety information for : Coccidioides immitis :
    • Biosafety Level: 2 and 3 -- Biosafety Level 2 practices and facilities are recommended for handling and processing clinical specimens, identifying isolates, and processing animal tissues. Animal Biosafety Level 2 practices and facilities are recommended for experimental animal studies when the route of challenge is parenteral. Biosafety Level 3 practices and facilities are recommended for propagating and manipulating sporulating cultures already identified as C. immitis and for processing soil or other environmental materials known or likely to contain infectious arthroconidia (US Dept. Health and Human Services, 1999)
    • Applicable: BIOSAFETY LEVEL 2 is similar to Biosafety Level 1 and is suitable for work involving agents of moderate potential hazard to personnel and the environment. It differs from BSL-1 in that (1) laboratory personnel have specific training in handling pathogenic agents and are directed by competent scientists; (2) access to the laboratory is limited when work is being conducted; (3) extreme precautions are taken with contaminated sharp items; and (4) certain procedures in which infectious aerosols or splashes may be created are conducted in biological safety cabinets or other physical containment equipment. BIOSAFETY LEVEL 3 is applicable to clinical, diagnostic, teaching, research, or production facilities in which work is done with indigenous or exotic agents which may cause serious or potentially lethal disease as a result of exposure by the inhalation route. Laboratory personnel have specific training in handling pathogenic and potentially lethal agents, and are supervised by competent scientists who are experienced in working with these agents. All procedures involving the manipulation of infectious materials are conducted within biological safety cabinets or other physical containment devices, or by personnel wearing appropriate personal protective clothing and equipment. The laboratory has special engineering and design features (US Dept. Health and Human Services, 1999).
    • Precautions:
      • Eating, drinking, smoking, handling contact lenses, and applying cosmetics are not permitted in the laboratory. All cultures, stocks, and other regulated wastes are decontaminated before disposal by an approved decontamination method, such as autoclaving. Laboratory personnel receive the appropriate immunizations or tests for the agents handled or potentially present in the laboratory (e.g., hepatitis B vaccine or TB skin testing), and periodic testing as recommended for the agent being handled. A high degree of precaution must always be taken with any contaminated sharp items, including needles and syringes, slides, pipettes, capillary tubes , and scalpels. All open manipulations involving infectious materials are conducted in biological safety cabinets or other physical containment devices within the containment module. Spills and accidents that result in overt or potential exposures to infectious materials are immediately reported to the laboratory director. Appropriate medical evaluation, surveillance, and treatment are provided and written records are maintained (US Dept. Health and Human Services, 1999).
    • Disposal:
      • Spills of infectious materials are decontaminated, contained and cleaned up by appropriate professional staff, or others properly trained and equipped to work with concentrated infectious material. Spill procedures are developed and posted. Contaminated equipment must be decontaminated before removal from the facility for repair or maintenance or packaging for transport, in accordance with applicable local, state, or federal regulations (US Dept. Health and Human Services, 1999).
B. Culturing Information:
  1. Culture methods for pathogenic mold :
    1. Description: The fungus grows on almost all routine laboratory media with or without antibiotics. Because of the hazards inherent in culture work, the use of Petri dishes is not advised without special precautions. Material to be examined can be spread on slants or bottles of Saubouraud?s agar and incubated at room temperature. Growth usually occurs by the third to fourth day, and conidiation by the tenth to 14th day. If subcultures are to be done, they should be made in a gloved isolation hood. When the culture is ready for examination, formaldehyde may be poured over the slants (Rippon, 1988).

    2. Medium:
      1. Almost any routine media (Rippon, 1988).
    3. Optimal Temperature: 22C or 72F (Rippon, 1988)
    4. Note: Morphology: At first, it is moist, glabrous, and grayish, but the colony rapidly develops abundant, floccose, aerial mycelium that soon covers the slant. The mycelium is initially white, but usually becomes tan to brown with age (Rippon, 1988).
  2. Culture Methods for endosporulating spherule :
    1. Description: Spherules are most easily produced in liquid modified Converse medium (MCM) with CO2 added at 37C, or better yet at 40C. Some spherule formation can be seen in agar slants 40C using a variety of media, however. The MCMA of Brosbe is probably the best medium for initiation and propagation of the spherule stage of C. immitis (Rippon, 1988).

    2. Medium:
      1. Modified Converse Medium (Rippon, 1988)
    3. Optimal Temperature: 37C (Rippon, 1988)
    4. Upper Temperature: 40C (Rippon, 1988)
    5. Note: Morphology: Numerous soil fungi have similar morphology at 25C, only C. immitis converts to the endosporulating spherule at 37 to 40C in culture or in experimentally infected animals (Rippon, 1988).
C. Diagnostic Tests :
  1. Organism Detection Tests:
    1. Fluorescent Microscopy:
      1. Ontology: UMLS:xxx
      2. Time to Perform: unknown
      3. Description: FA methods have been used for the detection of both C. immitis in infected tissue and antibody in human sera. Histologic staining was accomplished by preparing antisera in rabbits injected with viable or nonviable arthroconidia of C. immitis. The globulin fraction was separated from the sera and conjugated with fluorescein isothiocyanate. With this conjugate, endospores and the contents of spherules fluoresced but the walls of spherules in infected tissues did not, perhaps because antibody was already present on the surface of spherules in vivo. However, the walls of spherules produced in vitro did react with the fluorescein-labeled antibody. This reagent provided a sensitive histologic method for the detection of C. immitis in tissue and exudates. Its specificity was enhanced by prior adsorption with yeast cells of Histoplasma capsulatum or by diluting antibody globulin induced by injection of rabbits with viable (but not with killed) C. immitis arthroconidia. The one-step FA inhibition test was used to detect the presence of coccidioidal antibody in human sera. Smears of endospores prepared from the cut surface of infected mouse lungs were exposed to a mixture (A) of fluorescein-labeled rabbit antibody plus unlabeled unknown serum. The intensity of staining was compared with that of endospores exposed to a mixture (B) of fluorescein-labeled globulin and normal serum (the negative control). In A, coccidioidal antibody in the patient serum inhibited the uptake of the fluorescent tag by endospores. The FA inhibition test showed a 93% correlation with CF-positive sera and was positive with sera from some cases of coccidioidomycosis that were negative by CF as well as some that were reactive only by TP (Pappagianis and Zimmer, 1990).

  2. Immunoassay Tests:
    1. TP test:
      1. Ontology: UMLS:xxx
      2. Time to Perform: 1-to-2-days
      3. Description: The TP test is carried out by adding 0.2 ml of serum to 0.2 ml of coccidioidin solution. Antigen compared with a reference lot of antigen should be of such a concentration that undiluted and 1:10 dilutions of antigen will react with known TP-positive sera. Smith et al. originally included 1:40 and 1:100 dilutions of antigens to cover the "zone of equivalence" usually expected in a quantitative precipitin test, but these are not required. As a control, the patient's serum is added to culture medium similar to that in which coccidioidin was produced. The tubes are then shaken vigorously and placed in the 35C incubator. The test has incorrectly been described as one in which antigen is overlaid on the serum. The tubes are incubated for 24 h and then examined for presence of a translucent gelatinous button of precipitate by flicking the tube sharply to dislodge the button from the bottom of the tube. If no reaction is noted, the tubes are incubated again and read daily for the next 3 days. In 85 to 90% of instances, the TP test will show a precipitate in 24 h; only rarely will a reaction not be evident within 48 h. Although various dilutions of antigen have been used, the TP test has not been clearly standardized as a quantitative test. Presence or absence of TP reactivity is significant. The TP test is no longer recommended because of the greater sensitivity of the IDTP (Pappagianis and Zimmer, 1990).
    2. ID double diffusion test (Ouchterlony test) (Pappagianis and Zimmer, 1990):
      1. Ontology: UMLS:xxx
      2. Time to Perform: 1-to-2-days
      3. Description: In 1958, the double diffusion (Ouchterlony test) was shown to yield a band of precipitate when coccidioidin was diffused through agar toward serum from a patient with coccidioidomycosis. Subsequently, multiple bands of precipitation were obtained when various fractions derived from coccidioidin were tested against sera from patients with coccidioidomycosis. Huppert and Bailey developed the ID so that it could be used to detect antibody that correlated with CF (the IDCF) and TP (the IDTP). They used culture filtrate antigen solution (FAS or F) for the IDCF test and toluene lysate antigen solution (LAS or L) for the IDTP test, but in reality either of these antigen solutions can detect both kinds of antibody. The antigen solutions were concentrated, washed by ultrafiltration, and titrated to obtain the optimal dilution for serologic tests. However, Huppert et al. indicated that ultrafiltration removed most of the TP antigen. Based on the earlier observations of Smith et al. that the TP antigen is heat stable, Huppert and Bailey heated the toluene or lysate antigen to 60C for 30 min to inactivate CF (or IDCF) antigen. Their ID tests were carried out in 50-mm plastic petri dishes containing 5 ml of agar. Seven wells, 4.5 mm in diameter, were cut in the agar in a hexagonal pattern with one well in the center. The wall to wall distance between wells was 5 mm. The volume required per well was 40 to 50 RI. Other methods such as that of Kaufman and colleagues permit the testing of smaller volumes of many specimens in a single 90-mm petri dish. The serum (or other body fluid) is placed in the appropriate well and allowed to prediffuse at room temperature for 2 h, followed by addition of the appropriate antigen dilution. This prediffusion may be unnecessary for the detection of the IDCF reaction but appears essential in order to have the IDTP reaction, which is dependent on slowly diffusing IgM, occur approximately midway between serum and antigen wells. In our experience with concentrated specimens, 85 to 90% of reactions detectable by ID are apparent in 24 h, most of the remainder becoming detectable within 48 h. Only infrequently does a reaction appear with longer incubation. Nevertheless, we recommend that final readings be made at 96 h. The substrate for ID tests can be agar, agarose, or gellan gum, a polysaccharide produced by a Pseudomonas species. We have used the last agent for over 3 years (approximately 20,000 specimens tested) and have found it a satisfactory substitute for agar or agarose when testing human and animal sera. (Rabbit serum, however, may not show the same reactions in gellan gum that it does in agar.) (Pappagianis and Zimmer, 1990)
    3. LA test:
      1. Ontology: UMLS:xxx
      2. Time to Perform: 1-to-2-days
      3. Description: For the LA test, latex particles are coated with coccidioidal antigen obtained by toluene autolysis of mycelial C. immitis or from culture filtrates. Originally, polystyrene latex particles 0.15 to 0.35 um in diameter were used, but in more recent preparations 0.8-gm particles are used. The antigen solution is heated at 60C to inactivate the antigenic components) reactive with complement. The commercial distributors also have recommended that the serum to be tested be heated at 56C for 30 min to inactivate complement. Agglutination is read after 4 min. The LA test is more sensitive than TP, but it has yielded at least 6% false-positive reactions. Results of LA tests reported to us from several different laboratories indicate that, in general use, the rate of false-positives is higher. Because of this, a confirmatory test(s), preferably ID, must follow any positive LA. Very high rates of false-positive LA occur with CSF or with sera that have been diluted whether obtained from patients with coccidioidomycosis or not. Because of this, the attempted application of LA as a quantitative test is likely to provide spurious information. While the LA test is designated as a test to detect antibody (IgM) corresponding to that detectable by TP, our experience shows that some LA-positive reactions are reported with sera that are positive by IDCF (IgG) but not for IgM. The LA test has been useful in diagnosis of coccidioidomycosis in the dog (Pappagianis and Zimmer, 1990).
      4. False Positive: 6% -- The LA test is more sensitive than TP, but it has yielded at least 6% false-positive reactions (Pappagianis and Zimmer, 1990).
    4. CF test:
      1. Ontology: UMLS:xxx
      2. Time to Perform: unknown
      3. Description: To develop a standardized procedure that could be universally adopted, comparisons of different complement-fixation (CF) methods were carried out. The Smith CF macromethod, using overnight binding of complement at 4 to 5C, gave more reproducible results than the LBCF procedure (also using complement binding at 5C) in either its macro- or microdilution version. In the LBCF, the last tube or well showing 30% or less hemolysis is considered positive. The micro-LBCF requires approximately one-tenth the volume of serum, CSF, or other fluid required by the Kolmer or macro-LBCF, and it has been widely adopted. No direct comparison between the micro-LBCF and the original method of Smith et al. has been reported; however, binding at 4C provides higher titers than 2-h binding at 37C. In some instances, positive results are obtained after overnight test incubation at 4C but not at 37C after 2 h. As ordinarily described, the LBCF titration may begin with a 1:8 dilution of serum. Therefore, sera that are positive but only with titers of 2 or 4 would appear negative at the 1:8 dilution. Such low titers may be encountered in early coccidioidal disease, limited dissemination, pulmonary residua, or late disease when the titer has declined. The LBCF should begin with a 1:2 dilution if the IDCF is positive. Because CF titers of 2 to 8 may represent antibody reacting with another, cross-reactive antigen, the presence of coccidioidal CF antibody should be verified in the initial specimen by the more specific ID test (Pappagianis and Zimmer, 1990).
    5. IDCF test:
      1. Ontology: UMLS:xxx
      2. Time to Perform: unknown
      3. Description: The evolution and use of the ID test have been described above. In 1962, Schubert and Hampson showed that CF-positive sera reacted in an ID test with coccidioidin as antigen. Huppert and Bailey set forth appropriate conditions for the performance of the IDCF, which detected antibody corresponding to that detected by CF. The test relied on selection of the appropriate dilution of antigen, known to be heat labile, for the detection of IDCF. The dilution of antigen chosen, after 2-h prediffusion, yields a precipitate with antibody approximately midway between the wells. The IDCF test can be carried out without prediffusion of the serum. The higher the concentration of antibody, the closer to the antigen well will be the antigen-antibody precipitate. The location of the precipitate can even provide a rough estimate of how many dilutions of serum may be needed to obtain the endpoint titer in the CF test. While many coccidioidal sera yield a positive IDCF result without prior concentration, some specimens, e.g., from well-focalized pulmonary nodules or cavities, will not show IDCF reaction unless concentrated first. A control CF-positive human serum is used in each test (Pappagianis and Zimmer, 1990).
    6. QID test:
      1. Ontology: UMLS:xxx
      2. Time to Perform: 2-to-7-days
      3. Description: The QID test for IDCF antibody is carried out by diffusing various dilutions of serum against a fixed concentration of antigen previously determined to have appropriate reactivity. Several workers have studied the QID. By refilling the antigen and serum wells 24 and 48h after the original filling and taking a final reading at 72 h, Wieden et al. found that agreement between QID and CF titers (?1 two-fold dilution) was 84.7%. The QID was tested with consecutive sera from the same patients. Although it tended to yield slightly lower titers than the CF test performed by 2-h binding of complement at 37C, over time the changes in titer were comparable. Others found similar agreement between CF and QID tests: 80% , 87%, and 82%. The QID test requires fewer reagents and smaller volumes than the CF test. The manipulations are simpler, but no automation has been used and the results are delayed (final reading after 48 to 72 h). The QID test is practical for the laboratory that carries out few serologic determinations, but for large numbers of specimens the CF test is more practical. QID is needed when serum is anticomplementary and will not yield a readable titer by CF (frequent with canine sera) and for those unusual sera that do not show fixation of complement but yield a titer by QID (Pappagianis and Zimmer, 1990).
    7. Counterimmunoelectrophoresis:
      1. Ontology: UMLS:xxx
      2. Time to Perform: 1-hour-to-1-day
      3. Description: CIE has been used for both qualitative and quantitative antibody determination. With coccidioidin as antigen, both IDTP and IDCF antibodies were detected in sera of dogs with coccidioidomycosis. All canine sera that were positive by CF (titers, 2 to 128) were positive by CIE. Human sera and CSF were tested by CIE, using spherulin; the CIE provided 100% correlation with ID and 98% correlation with CF results. The mean titer by CIE was 1 serial dilution lower than that obtained by CF. The nature of the antigens used in two other studies is uncertain as one referred to a "toluene extract of culture filtrates" (82) and the other referred to "spherule coccidioidin". The former study found that 100% of sera with CF titers of >16 were positive by CIE, but at lower CF titers CIE was proportionately less sensitive, detecting only 64% when the titer was 2. As Kozub et al. pointed out, the sensitivity of the CIE would probably be improved by appropriate selection of reagents. However, if the sensitivity does not exceed that of ID, the advantage of more rapid results by CIE (1 to 2 h) may be of particular importance only in the infrequent cases of rapidly progressing coccidioidomycosis (Pappagianis and Zimmer, 1990).
    8. Radioimmunoassay:
      1. Ontology: UMLS:xxx
      2. Time to Perform: unknown
      3. Description: A solid-phase RIA method was tested by Catanzaro and Flatauer as a means of detecting antibody in human sera. RIA values correlated well with the clinical status of patients with pulmonary coccidioidomycosis (type of pulmonary disease not given) and with the CF titer in disseminated infections (Pappagianis and Zimmer, 1990).
    9. ELISA:
      1. Ontology: UMLS:xxx
      2. Time to Perform: unknown
      3. Description: Several groups of workers have studied detection of coccidioidal antibody by ELISA. A consistent shortcoming, found in about 10% of sera tested, is the inability to distinguish clearly between patient (positive) and control (negative) sera, as determined by conventional tests. Thus far, the closest correlation has been obtained between IDTP and ELISA. In a study of 792 sera, Leonard and Talbot reported an 89% agreement between ELISA and the TP test but 100% agreement between IDTP and ELISA, using anti-human globulin as the secondary antibody. In a separate study, Talbot et al. found that a large number of patients had CSF antibodies detectable by ELISA but not by CF. None of these patients ever developed coccidioidal meningitis, indicating that the greater sensitivity of the ELISA makes it unreliable for the detection of meningitis. This finding resembles that noted earlier for IDCF tests with concentrated CSF. The IDCF was overly sensitive because it detected IgG antibody in the CSF of patients with nonmeningitic coccidioidomycosis. Cole et al. tested antibody response to an isolated immunoreactive spherule wall antigen. Using anti-IgM in the ELISA they found overlapping optical density values between sera from patients and controls. When anti-IgG was the detecting antibody, there was clear differentiation between CF-positive and -negative sera; however, there was no correlation between CF titers and ELISA values, as noted also by Lindsay et al. We recently studied various coccidioidin, spherule-endospore, and synthetic (3-O-methylmannose-based) antigens in the conduct of coccidioidal ELISA, using 400 sera. The use of 20% normal goat serum as an ELISA diluent rather than traditional phosphate-buffered saline with Tween 20 provided a better distinction between IDTP-positive and -negative sera and a 97% correlation between ELISA and IDTP in serum when anti-IgM was used. Levels of anticoccidioidal IgG did not correlate with CF activity regardless of ELISA reagents (Pappagianis and Zimmer, 1990).
    10. Cloned epitope specific to Complement-Fixing Antibody:
      1. Ontology: UMLS:xxx
      2. Time to Perform: unknown
      3. Description: This investigation is the first to show that the C. immitis CF/chitinase protein contains a domain that is specific for anti-Coccidioides CF antibody. This domain, comprised of amino acid residues 20 through 310, detected antibody in 21 (95%) of 22 serum samples from coccidioidomycosis patients and was without reactivity with serum samples from 20 histoplasmosis patients, 15 patients with blastomycosis, and 14 normal subjects. Preincubation of reference IDCF antibody serum with peptide 20-310 ablated its reactivity in the IDCF assay, thereby confirming that the peptide contains the CF reactive epitope. Antibody reactivity to peptide 20-310 is predominantly of the IgG1 isotype and is directed against a heatlabile peptide epitope (Yang et al., 1997)
      4. False Positive: 0% (Yang et al., 1997)
      5. False Negative: 5% (Yang et al., 1997)

  3. Nucleic Acid Detection Tests: :
    1. Soil Isolation (Greene et al., 2000):
      1. Ontology: UMLS:xxx
      2. Time to Perform: 1-hour-to-1-day
      3. Description: The fungal pathogen Coccidioides immitis, causative agent of coccidioidomycosis or Valley Fever, was first isolated from the environment in 1932. It has been isolated on numerous occasions since then, but always with the use of a mammalian host. The morphology of C. immitis is indistinct from related species, thus, its identification hinges upon its ability to infect and produce spherules in a susceptible animal. In this study, four genetically distinct isolates of C. immitis were isolated from soil samples from the San Joaquin Valley without the use of a host. None of these sites had been definitively associated with human infection. The isolates were identified from over 2400 soil isolates from 720 soil samples using C. immitis specific primers based on the ITS sequence of ribosomal DNA. They were further typed using molecular markers available for clinical isolates of C. immitis (Greene et al., 2000).
      4. Primers:
    2. ITS1 and ITS4 based PCR-EIA test (Lindsley et al., 2001):
      1. Ontology: UMLS:xxx
      2. Time to Perform: 1-hour-to-1-day
      3. Description: Universal fungal primers ITS1 and ITS4, directed to the conserved regions of ribosomal DNA, were used to amplify DNA from Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, Paracoccidioides brasiliensis, Penicillium marneffei, Sporothrix schenckii, Cryptococcus neoformans, five Candida species, and Pneumocystis carinii. Specific oligonucleotide probes to identify these fungi, as well as a probe to detect all dimorphic, systemic pathogens, were developed. PCR amplicons were detected colorimetrically in an enzyme immunoassay format. These fungi could be differentiated by a process of elimination. In conclusion, probes developed to yeast-like pathogens were found to be highly specific and should prove to be useful in differentiating these organisms in the clinical setting (Lindsley et al., 2001).
      4. Primers:
    3. Molecular Probes for Diagnosis of Fungal Infections (derived from 28S rRNA) (Sandhu et al., 1995):
      1. Ontology: UMLS:xxx
      2. Time to Perform: 1-hour-to-1-day
      3. Description: A section of the 28S rRNA gene from approximately 100 fungi, representing about 50 species of pathogens and commonly encountered saprophytes, was sequenced to develop universal PCR primers and species-specific oligonucleotide probes. Each step in the process of detection and identification was standardized to a common set of conditions applicable without modification to all fungi of interest and all types of clinical specimens. These steps consist of DNA extraction by boiling specimens in an alkaline guanidine-phenol-Tris reagent, amplification of a variable region of the 28S rRNA gene with universal primers, and amplicon identification by probe hybridization or DNA sequencing performed under conditions identical for all fungi. The results obtained by testing a panel of fungal isolates and a variety of clinical specimens indicate a high level of specificity (Sandhu et al., 1995).
      4. Primers:
      5. False Positive: 0% : No false-positive results were observed, indicating a specificity of 100% for all 21 probes within the selected test panel of organisms (Sandhu et al., 1995).
      6. False Negative: 0% - 20% when sufficient DNA was available: The sensitivity of our primers U1 and U2 was evaluated by amplifying 28S rDNA from known amounts of serially diluted genomic DNA obtained from S. cerevisiae. Primers U1 and U2 successfully amplified the appropriate region of the 28S rRNA gene from the equivalent of as little as 0.2 genomes. Additionally, the 2 specimens containing C. immitis as well as the two containing C. neoformans were correctly identified. This indicated a detection sensitivity ranging from approximately 80 to 100% within this limited although diverse group of specimens (Sandhu et al., 1995).

    4. RFLP genotyping (Zimmermann et al., 1994):
      1. Ontology: UMLS:xxx
      2. Time to Perform: 2-to-7-days
      3. Description: In the past, it has been possible to distinguish isolates of C. immitis from various patients and geographic locations by phenotypic characteristics. However, little is known of the extent of genetic variation within C. immitis at the DNA sequence level. The ability to distinguish genotypes of isolates would be useful in investigating the source(s) of outbreaks of infection and in defining the relatedness of isolates recovered from different patients. As a first step, we used restriction fragment length polymorphisms (RFLPs) to compare different C. immitis isolates. Fifteen isolates of C. immitis were examined. our results indicated that there were two main groups of C. immitis distinguishable by RFLP analysis; these groups included isolates that caused clinically apparent disease during the epidemic years 1991 and 1992. In humans, because there were a variety of outcomes for disease caused by the isolates, it was not possible to associate virulence with either of the groups of isolates (Zimmermann et al., 1994).
    5. SNP and Microsatellite genotyping (Fisher et al., 1999):
      1. Ontology: UMLS:xxx
      2. Time to Perform: unknown
      3. Description: Here, we have described the isolation of two sets of polymorphic genetic markers, one based on SNPs and the other on microsatellites, from the pathogenic fungus C. immitis. We are currently using these markers to generate data sets from panels of C. immitis that were isolated from clinical and environmental sources from a range of geographical locations spanning the entire distribution of this pathogen. Used together, these data will enable recent epidemiological patterns to be characterized, as well as analysis of deeper evolutionary processes (Fisher et al., 1999).

  4. Other Types of Diagnostic Tests:
    1. Coccidioidin Skin Test (Ampel, 2003):
      1. Ontology: UMLS:xxx
      2. Time to Perform: 1-to-2-days
      3. Description: Measurement of cellular immune response in human coccidioidomycosis, a disease of the Western Hemisphere caused by the soil-dwelling fungus Coccidioides, began more than 75 years ago. Numerous studies have shown that measurement of coccidioidal cellular immunity is a useful epidemiologic and clinical tool. The first widely used coccidioidal skin-test reagent, coccidioidin, was derived from a filtrate of cultured mycelia of Coccidioides by Smith and colleagues in the 1940?s (Ampel, 2003).
      4. False Positive: In these early studies, there was evidence of cross-reactions in those with histoplasmosis. In addition, cross reactions with blastomycin were also seen, but cross reactions to tuberculin were not observed (Ampel, 2003).
      5. False Negative: Smith and colleagues were also able to demonstrate that persons with disseminated coccidioidomycosis were less likely to express delayed reaction to coccidioidin than subjects with localized disease or those who were asymptomatic. Among 100 subjects with dissemination, only 30 reacted to 1:100 coccidioidin (Ampel, 2003).
    2. Spherulin Skin Test (Ampel, 2003):
      1. Ontology: UMLS:xxx
      2. Time to Perform: 1-to-2-days
      3. Description: Coccidioidin remained the standard until the 1970?s, when spherulin, obtained from the spherule form of the fungus, was found to be more sensitive (Ampel, 2003). Kong and colleagues then showed that a filtered preparation from in vitro cultured spherules, called spherulin, could also induce delayed-type hypersensitivity in immunized or infected mice, but with a high incidence of severe inflammation soon after injection. This preparation was subsequently modified by Levine and coworkers, who were then able to elicit delayed cutaneous hypersensitivity in mice and guinea pigs that had been either previously immunized or infected with Coccidioides. Moreover, this material was found to elicit stronger reactions of longer duration than mycelial-derived coccidioidins, including Smith?s Lot 64 (Ampel, 2003).
      4. False Positive: Among 10 subjects who reacted to 2.8 ?g spherulin but not to coccidioidin, only two were also reactive to histoplasmin. Another study demonstrated that 2.8 ?g spherulin gave cross reactions in histoplasmin responders in fewer than 1% of cases (Ampel, 2003).
      5. False Negative: Among 23 subjects with clinically active disseminated disease, positive reactions to spherulin occurred in 17, but only nine responded to mycelial-based coccidioidin. In these subjects, there was no association between the skin-test response and severity of clinical disease, coccidioidal serologic titer, or race. Among 18 subjects with healed, clinically inactive pulmonary coccidioidomycosis, 17 reacted to spherulin and 12 reacted to coccidioidin (Ampel, 2003).

V. References

A. Journal References:
Abadi et al., 1995: Abadi J Amphotericin B. Pediatr Rev. 1995; 16(10): 363 - 364. [PubMed: 7479429].
Ampel, 2003: Ampel NM Measurement of cellular immunity in human coccidioidomycosis. Mycopathologia. 2003; 156(4): 247 - 262. [PubMed: 14682448].
Barnato et al., 2001: Barnato AE, Sanders GD, Owens DK Cost-effectiveness of a potential vaccine for Coccidioides immitis. Emerg Infect Dis. 2001; 7(5): 797 - 806. [PubMed: 11747691].
Burt et al., 1996: Burt A, Carter DA, Koenig GL, White TJ, Taylor JW Molecular markers reveal cryptic sex in the human pathogen Coccidioides immitis. Proc Natl Acad Sci U S A. 1996; 93(2): 770 - 773. [PubMed: 8570632].
Cairns et al., 2000: Cairns L, Blythe D, Kao A, Pappagianis D, Kaufman L, Kobayashi J, Hajjeh R Outbreak of coccidioidomycosis in Washington state residents returning from Mexico. Clin Infect Dis. 2000; 30(1): 61 - 64. [PubMed: 10619734].
Charlton et al., 1999: Charlton V, Ramsdell K, Sehring S Intrauterine transmission of coccidioidomycosis. Pediatr Infect Dis J. 1999 Jun;18(6):561-3. 1999; 18(6): 561 - 563. [PubMed: 10391194].
Chiller et al., 2003: Chiller TM, Galgiani JN, Stevens DA Coccidioidomycosis. Infect Dis Clin North Am. 2003; 17(1): 41 - 57. [PubMed: 12751260].
Cox and Magee et al., 2004: Cox RA, Magee DM Coccidioidomycosis: host response and vaccine development. Clin Microbiol Rev. 2004; 17(4): 804 - 839. [PubMed: 15489350].
Crum et al., 2002: Crum N, Lamb C, Utz G, Amundson D, Wallace M Coccidioidomycosis outbreak among United States Navy SEALs training in a Coccidioides immitis-endemic area-Coalinga, California. J Infect Dis. 2002; 186(6): 865 - 868. [PubMed: 12198626 ].
Deresinski, 2003: Deresinski S Coccidioides immitis as a potential bioweapon. Semin Respir Infect. 2003; 18(3): 216 - 219. [PubMed: 14505283].
Ellis, 2002: Ellis D Amphotericin B: spectrum and resistance. J Antimicrob Chemother. 2002; 49(Suppl 1): 7 - 10. [PubMed: 11801575].
Eulalio et al., 2001: Eulalio KD, de Macedo RL, Cavalcanti MA, Martins LM, Lazera MS, Wanke B Coccidioides immitis isolated from armadillos (Dasypus novemcinctus) in the state of Piaui?, northeast Brazil. Mycopathologia. 2001; 149(2): 57 - 61. [PubMed: 11270394].
Feldman and Snyder, 2001: Feldman BS, Snyder LS Primary pulmonary coccidioidomycosis. Semin Respir Infect. 2001; 16(4): 231 - 237. [PubMed: 11740823].
Fisher et al., 1999: Fisher MC, White TJ, Taylor JW Primers for genotyping single nucleotide polymorphisms and microsatellites in the pathogenic fungus Coccidioides immitis. Mol Ecol. 1999; 8(6): 1082 - 1084. [PubMed: 10434430].
Fisher et al., 2002: Fisher MC, Koenig GL, White TJ, Taylor JW Molecular and phenotypic description of Coccidioides posadasii sp. nov., previously recognized as the non-California population of Coccidioides immitis. Mycologia. 2002; 94(1): 73 - 84. [PubMed: NA].
Flynn et al., 1979: Flynn NM, Hoeprich PD, Kawachi MM, Lee KK, Lawrence RM, Goldstein E, Jordan GW, Kundargi RS, Wong GA An unusual outbreak of windborne coccidioidomycosis. N Engl J Med. 1979; 301(7): 358 - 361. [PubMed: 460324].
Galgiani, 1999: Galgiani JN Coccidioidomycosis: a regional disease of national importance. Rethinking approaches for control. Ann Intern Med. 1999; 130(4 Pt 1): 293 - 300. [PubMed: 10068388].
Galgiani et al., 2000: Galgiani JN, Ampel NM, Catanzaro A, Johnson RH, Stevens DA, Williams PL Practice guideline for the treatment of coccidioidomycosis. Infectious Diseases Society of America. Clin Infect Dis. 2000; 30(4): 658 - 661. [PubMed: 10770727].
Galgiani et al., 2000: Galgiani JN, Catanzaro A, Cloud GA, Johnson RH, Williams PL, Mirels LF, Nassar F, Lutz JE, Stevens DA, Sharkey PK, Singh VR, Larsen RA, Delgado KL, Flanigan C, Rinaldi MG Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group. Ann Intern Med. 2000; 133(9): 676 - 686. [PubMed: 11074900].
Ghannoum and Kuhn, 2002: Ghannoum MA, Kuhn DM Voriconazole -- better chances for patients with invasive mycoses. Eur J Med Res. 2002; 7(5): 242 - 256. [PubMed: 12069915].
Greene et al., 2000: Greene DR, Koenig G, Fisher MC, Taylor JW Soil isolation and molecular identification of Coccidioides immitis. Mycologia. 2000; 92(3): 406 - 410. [PubMed: NA].
Hagman et al., 2000: Hagman HM, Madnick EG, D'Agostino AN, Williams PL, Shatsky S, Mirels LF, Tucker RM, Rinaldi MG, Stevens DA, Bryant RE Hyphal forms in the central nervous system of patients with coccidioidomycosis. Clin Infect Dis. 2000; 30(2): 349 - 353. [PubMed: 10671340].
Holley et al., 2002: Holley K, Muldoon M, Tasker S Coccidioides immitis osteomyelitis: a case series review. Orthopedics. 2002; 25(8): 827 - 832. [PubMed: 12195909].
Kirkland and Fierer, 1996: Kirkland TN, Fierer J Coccidioidomycosis: a reemerging infectious disease. Emerg Infect Dis. 1996; 2(3): 192 - 199. [PubMed: 8903229].
Kohn et al., 1992: Kohn GJ, Linne SR, Smith CM, Hoeprich PD Acquisition of coccidioidomycosis at necropsy by inhalation of coccidioidal endospores. Diagn Microbiol Infect Dis. 1992; 15(6): 527 - 530. [PubMed: 1424506].
Lindsley et al., 2001: Lindsley MD, Hurst SF, Iqbal NJ, Morrison CJ Rapid identification of dimorphic and yeast-like fungal pathogens using specific DNA probes. J Clin Microbiol. 2001; 39(1): 3505 - 3511. [PubMed: 11574564].
Linsangan and Ross, 1999: Linsangan LC, Ross LA Coccidioides immitis infection of the neonate: two routes of infection. Pediatr Infect Dis J. 1999; 18(2): 171 - 173. [PubMed: 10048696].
Martino, 2004: Martino R Efficacy, safety and cost-effectiveness of Amphotericin B Lipid Complex (ABLC): a review of the literature. Curr Med Res Opin. 2004; 20(4): 485 - 504. [PubMed: 15119986].
Miller et al., 2004: Miller MB, Hendren R, Gilligan PH Posttransplantation disseminated coccidioidomycosis acquired from donor lungs. J Clin Microbiol. 2004; 42(9): 2347 - 2349. [PubMed: 15131231].
MMWR, 2001a: Coccidioidomycosis in Workers at an Archeologic Site ? Dinosaur National Monument, Utah, June?July 2001. MMWR Morb Mortal Wkly Rep. 2001; 50(45): 1005 - 1008. [PubMed: 11724157].
MMWR, 2001b: Coccidioidomycosis among persons attending the world championship of model airplane flying--Kern County, California, October 2001. MMWR Morb Mortal Wkly Rep. 2001; 50(49): 1106 - 1107. [PubMed: 11794620].
Pappagianis, 1993: Pappagianis D Evaluation of the protective efficacy of the killed Coccidioides immitis spherule vaccine in humans. The Valley Fever Vaccine Study Group. Am Rev Respir Dis. 1993; 148(3): 656 - 660. [PubMed: 8368636].
Pappagianis, 1994: Pappagianis D Marked increase in cases of coccidioidomycosis in California: 1991, 1992, and 1993. Clin Infect Dis. 1994; 19(Suppl 1): S14 - S18. [PubMed: 7948566].
Pappagianis and Zimmer, 1990: Pappagianis D, Zimmer BL Serology of coccidioidomycosis. Clin Microbiol Rev. 1990; 3(3): 247 - 268. [PubMed: 2200605].
Pier et al., 2000: Pier AC, Cabanes FJ, Chermette R, Ferreiro L, Guillot J, Jensen HE, Santurio JM Prominent animal mycoses from various regions of the world. Med Mycol. 2000; 38(Suppl 1): 47 - 28. [PubMed: 11204164 ].
Sandhu et al., 1995: Sandhu GS, Kline BC, Stockman L, Roberts GD Molecular probes for diagnosis of fungal infections. J Clin Microbiol. 1995; 33(11): 2913 - 2919. [PubMed: 8576345].
Schneideret al., 1997: Schneider E, Hajjeh RA, Spiegel RA, Jibson RW, Harp EL, Marshall GA, Gunn RA, McNeil MM, Pinner RW, Baron RC, Burger RC, Hutwagner LC, Crump C, Kaufman L, Reef SE, Feldman GM, Pappagianis D, Werner SB A coccidioidomycosis outbreak following the Northridge, Calif, earthquake. JAMA. 1997; 277(11): 904 - 908. [PubMed: 9062329].
Sewell, 1995: Sewell DL Laboratory-associated infections and biosafety. Clin Microbiol Rev. 1995; 8(3): 389 - 405. [PubMed: 7553572].
Sorensen et al., 1999: Sorensen KN, Clemons KV, Stevens DA Murine models of blastomycosis, coccidioidomycosis, and histoplasmosis. Mycopathologia. 1999; 146(2): 53 - 65. [PubMed: 10822504].
Stevens, 1995: Stevens DA Coccidioidomycosis. N Engl J Med. 1995; 332(16): 1077 - 1082. [PubMed: 7898527].
Stevens, 2002: Stevens DA Diagnosis of fungal infections: current status. J Antimicrob Chemother. 2002; 49(Suppl 1): 11 - 19. [PubMed: 11801576].
Teel et al., 1970: Teel KW, Yow MD, Williams TW Jr A localized outbreak of coccidioidomycosis in southern Texas. J Pediatr. 1970; 77(1): 65 - 73. [PubMed: 5465361].
Terio et al., 2003: Terio KA, Stalis IH, Allen JL, Stott JL, Worley MB Coccidioidomycosis in Przewalski's horses (Equus przewalskii). J Zoo Wildl Med. 2003; 34(4): 339 - 345. [PubMed: 15077708].
Wanke et al., 1999: Wanke B, Lazera M, Monteiro PC, Lima FC, Leal MJ, Ferreira Filho PL, Kaufman L, Pinner RW, Ajello L Investigation of an outbreak of endemic coccidioidomycosis in Brazil's northeastern state of Piaua? with a review of the occurrence and distribution of Coccidioides immitis in three other Brazilian states. Mycopathologia. 1999; 148(2): 57 - 67. [PubMed: 11220226].
Woods et al., 2000: Woods CW, McRill C, Plikaytis BD, Rosenstein NE, Mosley D, Boyd D, England B, Perkins BA, Ampel NM, Hajjeh RA Coccidioidomycosis in human immunodeficiency virus-infected persons in Arizona, 1994-1997: incidence, risk factors, and prevention. J Infect Dis. 2000; 181(4): 1428 - 1438. [PubMed: 10753734].
Yang et al., 1997: Yang MC, Magee DM, Cox RA Mapping of a Coccidioides immitis-specific epitope that reacts with complement-fixing antibody. Infect Immun. 1997; 65(10): 4068 - 4074. [PubMed: 9317009].
Zimmermann et al., 1994: Zimmermann CR, Snedker CJ, Pappagianis D Characterization of Coccidioides immitis isolates by restriction fragment length polymorphisms. J Clin Microbiol. 1994; 32(12): 3040 - 3042. [PubMed: 7883896].
B. Book References:
Miyaji, 1987: Brummer E, Clemons KV Animal Models of Systemic Mycoses. 84 - 87. In: Miyaji M Animal Models in Medical Mycology1987. CRC Press, Inc., Boca Raton, Florida.
Rippon, 1988: Rippon JW Coccidioidomycosis. 433 - 473. In: Wonsiewicz M Medical Mycology, The Pathogenic Fungi and the Pathogenic Actinomycetes1988. W. B. Saunders Company - Harcourt Brace Jaovanovich, Inc., Philadelphia, Pennsylvania.
US Dept. Health and Human Services, 1999: U.S. Department of Health and Human Services , Centers for Disease Control and Prevention , National Institutes of Health 1 - 265. In: Richmond JY, McKinney RW Biosafety in Microbiological and Biomedical Laboratories, 4th edition1999. U.S. Government Printing Office, Washington DC.
C. Website References:
Coccidioides Sequencing Project Website: Coccidioides immitis Sequencing Project [ http://www.broad.mit.edu/annotation/fungi/coccidioides_immitis/index.html ].
Coccidioides Sequencing Project Website-FAQ: Coccidioides immitis Sequencing Project - FAQ [ http://www.broad.mit.edu/annotation/fungi/coccidioides_immitis/faq.html ].
GenBank entry for Tube Precipitin: AF022893 - Coccidioides immitis [gi:6648593] [ http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=nucleotide&val=6648593 ].
Website 1: Coccidioides immitis [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=5501&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 2: Coccidioides immitis RS [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=246410&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 3: Human (Homo sapiens) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9606&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 4: Nine-banded Armadillo (Dasypus novemcinctus) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9361&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 5: Przewalski's horse (Equus przewalskii) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9798&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 6: House mouse (Mus musculus) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10090&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 7: Crab-eating Macaque (Macaca fascicularis) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9541&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 8: Rhesus Monkey (Macaca mulatta) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9544&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 9: Guinea Pig (Cavia porcellus) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=10141&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 10: Dog (Canis familiaris) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9615&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 11: Horse (Equus caballus) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9796&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 12: Cat (Felis catus) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9685&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 13: Cow (Bos taurus) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9913&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 14: Sheep (Ovis aries) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9940&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 15: Swine (Sus scrofa) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9823&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 16: Burro (Equus asinus) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9793&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 17: Coyote (Canis latrans) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9614&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 18: Rodents (Rodentia) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9989&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 19: Primates (Primates) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=9443&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 20: Serpents (Serpentes) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=8570&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
Website 21: Sea Otters (Enhydra lutris) [ http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&id=34882&lvl=3&lin=f&keep=1&srchmode=1&unlock ].
D. Thesis References:

No thesis or dissertation references used.


VI. Curation Information