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1. Summary, 602

2. Introduction, 602

3. Infection with Coccidioides immitis, 602

4. Treatment of coccidioidomycosis, 603

5. Incidence of coccidioidomycosis, 603

6. Development of vaccine, 603

7. Select Agent Rule, 603

8. References, 605

1. SUMMARY

  1. Top of page
  2. 1. SUMMARY
  3. 2. INTRODUCTION
  4. 3. INFECTION WITH COCCIDIOIDES IMMITIS
  5. 4. TREATMENT OF COCCIDIOIDOMYCOSIS
  6. 5. INCIDENCE OF COCCIDIOIDOMYCOSIS
  7. 6. DEVELOPMENT OF VACCINE
  8. 7. SELECT AGENT RULE
  9. References

Coccidioides immitis is the most virulent of the primary fungal pathogens of humans and other animals. As such, it is the only fungal aetiological agent designated as Biosafety Level 3 in Biosafety in Microbiological and Biomedical Laboratories, 3rd edn (Department of Health and Human Services 1993; http://www.nih.gov/od/ors/ds/pubs/bmbl/index.htm). Natural infection occurs via inhalation of aerosolized conidia from a primary environmental focus, and can also occur from traumatic implantation. In both instances, analogies can be drawn to Bacillus anthracis. Similarly, C. immitis was listed amongst the ‘Select Agents’ in the Final rule on Additional Requirements for Facilities Transferring or Receiving Select Agents in response to the US Antiterrorism and Effective Death Penalty Act of 1996 (Department of Health and Human Services 1996). Natural infection can resolve spontaneously following a primary pulmonary, flu-like episode, or can progress to a serious and life-threatening local or disseminated disease. Natural or experimental infection appears to confer immunity, and efforts are underway to develop a protective vaccine. Such would be a welcomed addition to the limited antifungal armamentarium.

2. INTRODUCTION

  1. Top of page
  2. 1. SUMMARY
  3. 2. INTRODUCTION
  4. 3. INFECTION WITH COCCIDIOIDES IMMITIS
  5. 4. TREATMENT OF COCCIDIOIDOMYCOSIS
  6. 5. INCIDENCE OF COCCIDIOIDOMYCOSIS
  7. 6. DEVELOPMENT OF VACCINE
  8. 7. SELECT AGENT RULE
  9. References

Coccidioides immitis is an endemic, systemic fungal pathogen of humans and other animals. The endemic mycoses are those that are defined by a well-circumscribed geographical area. For coccidioidomycosis, the disease caused by this fungus, the endemic regions in the United States are primarily in six states: Arizona, California, New Mexico, Nevada, Texas and Utah (http://www.arl.arizona.edu/vfce/). Endemic regions are also well known in Central and South America. The organism was described at the turn of the century by Posadas, who followed the case of an Argentinian soldier who went on to die and leave gross and histopathological specimens to history documenting the apparent first recognized case of disseminated disease. The binomial, Coccidioides immitis, was given to the organism because the parasitic, or spherule phase of the fungus in tissue resembled members of the protozoa from order Coccidia, and because the fatal consequences of the involved case (Coccididioides=Coccidium-like; immitis= not mild). The discipline of medical mycology has had a tendency to be viewed as exotic and distinct from the microbiological mainstream, and with its rich history of descriptive and botanical scholarly studies accumulated a terminology that led to slow assimilation into related fields of microbiology. Additionally, the similarity of the genus names of the fungus and the namesake coccidian parasite from which the current name is derived leads to malapropisms to the present day. Synonyms for the disease are Posadas’ disease in tribute to the history, and Valley Fever (or San Joaquin Valley) because of the high incidence and prevalence of disease in that region of California (Rippon 1988).

3. INFECTION WITH COCCIDIOIDES IMMITIS

  1. Top of page
  2. 1. SUMMARY
  3. 2. INTRODUCTION
  4. 3. INFECTION WITH COCCIDIOIDES IMMITIS
  5. 4. TREATMENT OF COCCIDIOIDOMYCOSIS
  6. 5. INCIDENCE OF COCCIDIOIDOMYCOSIS
  7. 6. DEVELOPMENT OF VACCINE
  8. 7. SELECT AGENT RULE
  9. References

Coccidioides immitis is distributed throughout desert regions of the endemic area in what is ecologically defined as the Lower Sonoran Life Zone. In the laboratory on culture media, and presumably in nature, the organism exists as a mould that ages to produce spores (arthroconidia) that separate in characteristic fashion via the disarticulation of the parent mycelium leaving the ruptured cell-wall fragments of adjacent cell remnants attached to opposing ends. The spores are of sufficiently small dimension to infect mammalian lungs as demonstrated experimentally in animal models of infection, and as documented accidentally through laboratory accidents involving the mycelial phase of the fungus. In vivo the spores enlarge to form spherules that are typically 20 microns or more in diameter when viewed in tissue sections of actively infected hosts. The spherules undergo internal divisions to yield endospores that are released upon maturation, and go on to repeat the cycle of the infection.

Infection of normal hosts with spores of C. immitis can result in a spectrum of consequences ranging from rapid clearance and resolution with no or minimal symptoms of disease, or can establish an active replicating cycle that includes profound pulmonary disease, and can include dissemination from the pulmonary focus via the bloodstream to involve multiple systems of the body. When dissemination occurs and is recognized clinically, the more common sites of involvement are the central nervous system (typically meningitis), skin, bone and multiple organs. Relative rates of the course of infection have been summarized as: subclinical pulmonary infection (65%); and acute pulmonary disease (35%; Galgiani 1993).

4. TREATMENT OF COCCIDIOIDOMYCOSIS

  1. Top of page
  2. 1. SUMMARY
  3. 2. INTRODUCTION
  4. 3. INFECTION WITH COCCIDIOIDES IMMITIS
  5. 4. TREATMENT OF COCCIDIOIDOMYCOSIS
  6. 5. INCIDENCE OF COCCIDIOIDOMYCOSIS
  7. 6. DEVELOPMENT OF VACCINE
  8. 7. SELECT AGENT RULE
  9. References

Treatment choices for coccidioidomycosis depend on the form and severity of disease. In normal hosts with newly detected, but low-grade infection that appears to be well contained by host defenses, the physician may recommend a ‘wait and watch’ approach.

For cases of acute disease requiring treatment, as well as treatment of chronic or progressive pulmonary disease, treatment options include Amphotericin B in either deoxycholate or lipid formulations, and azole antifungals such as fluconazole. Improvements have been made in the management of coccidioidomycosis, and many of the key clinical trials were conducted by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) Mycoses Study Group (funded by contract to the University of Alabama at Birmingham, W.E. Dismukes, principal investigator) and specifically through the subproject managed by J. Galgiani, principal investigator. In general, it is said that response of serious disease of the preceding types to be ‘moderate’, and relapse following therapy is high. Response of disseminated disease to available therapy is less good, especially when the meninges are involved. In one literature series of comparisons, the average survival response with Amphotericin B therapy was 57% (Galgiani 1993; range of 51–100%; see Labadie and Hamilton 1986).

5. INCIDENCE OF COCCIDIOIDOMYCOSIS

  1. Top of page
  2. 1. SUMMARY
  3. 2. INTRODUCTION
  4. 3. INFECTION WITH COCCIDIOIDES IMMITIS
  5. 4. TREATMENT OF COCCIDIOIDOMYCOSIS
  6. 5. INCIDENCE OF COCCIDIOIDOMYCOSIS
  7. 6. DEVELOPMENT OF VACCINE
  8. 7. SELECT AGENT RULE
  9. References

The incidence of coccidioidomycosis, based on extrapolations from skin test reactions, was estimated in 1983 at between 25 000 and 100 000 new infections per year by Drutz and Huppert (1983). The disease occurs in epidemic proportions. In one very well characterized and extended epidemic in California, there was a 10-fold increase between 1991 and 1992 to a total of more than 4000 cases reported to the California Department of Health. Most of the reported cases were from Kern County, CA; it was estimated that direct medical costs due to the disease in that county were approximately 45 million dollars between 1991 and 1993. Kern County is a well-known epicentre of the disease, but the preceding figures are probably underestimates and could reflect the local appreciation for the disease, the focus of diagnostic capability, and attentiveness to reporting (CDC 1993; CDC 1994; Pappagianis 1994; Kirkland and Fierer 1996).

6. DEVELOPMENT OF VACCINE

  1. Top of page
  2. 1. SUMMARY
  3. 2. INTRODUCTION
  4. 3. INFECTION WITH COCCIDIOIDES IMMITIS
  5. 4. TREATMENT OF COCCIDIOIDOMYCOSIS
  6. 5. INCIDENCE OF COCCIDIOIDOMYCOSIS
  7. 6. DEVELOPMENT OF VACCINE
  8. 7. SELECT AGENT RULE
  9. References

The natural history of coccidioidomycosis reflects that this is primarily a cell-mediated disease, and that skin test conversion correlates with exposure and immunity to re-infection, although reactivation disease can occur. This observation along with lack of feasibility to eliminate exposure to natural infection, the magnitude of individual and community public health costs, the limitations of existing therapy, and the obvious advantages of vaccination as a prevention strategy have led numerous investigators to pursue a vaccine approach for coccidioidomycosis. Years of basic and preclinical studies led to a clinical trial of a formalin-killed spherule vaccine. Twenty-eight hundred human subjects were randomized 1 : 1 in a double blind, placebo-controlled trial of three doses of vaccine containing 1·75 mg of protein dose–1 vs. saline injected controls. The authors concluded that ‘A different physical form other than whole spherules must be sought to increase tolerability of the immunogenic component’ (Pappagianis and The Valley Fever Vaccine Study Group 1993). Two factors thwarted the study: (i) the low incidence of primary disease during the study period (only 13 cases of disease occurred in the placebo group and nine in the vaccinated group); and (ii) it became necessary to dilute the vaccine by many fold on a mg of protein kg–1 basis because of reactogenicity at the injection site (the final dose in humans was, on a mg/kg basis, approximately 0·1% of the immunizing dose in mice). The lead author of that published study, plus several other groups of investigators are aggressively pursuing contemporary vaccine efforts for this disease.

7. SELECT AGENT RULE

  1. Top of page
  2. 1. SUMMARY
  3. 2. INTRODUCTION
  4. 3. INFECTION WITH COCCIDIOIDES IMMITIS
  5. 4. TREATMENT OF COCCIDIOIDOMYCOSIS
  6. 5. INCIDENCE OF COCCIDIOIDOMYCOSIS
  7. 6. DEVELOPMENT OF VACCINE
  8. 7. SELECT AGENT RULE
  9. References

The ‘Select Agent Rule’ was enacted in the United States to ‘establish a system of safeguards to be followed when specific agents are transported; collect and provide information concerning the location where certain potentially hazardous agents are transferred; track the acquisition and transfer of these specific agents; and establish a process for alerting appropriate authorities if an unauthorized attempt is made to acquire these agents’ (Department of Health and Human Services 1996; see http://www.cdc.gov/od/ohs/lrsat/42cfr72.htm). A Select Agent list was established containing numerous biosafety level 3 (BSL3) or biosafety level 4 (BSL4) bacteria and viruses (Table 1). Coccidioides immitis is classified as BSL3 and is the only fungus on the Select Agent list. ‘Biosafety Level 3 (BSL3) practices and facilities are recommended for propagating and manipulating sporulating cultures already identified as C. immitis and for processing soil or environmental materials known or likely to contain infectious conidia’ (http://www.nih.gov/od/ors/ds/pubs/bmbl/contents.htm;Department of Health and Human Services 1993).

Table 1.   Representative Select Agents from Appendix A to 42 CFR Part 72 – The ‘Select Agent Rule’* Thumbnail image of

Surveillance is a key defensive measure in recognition of a bioterrorist event. Coccidioides immitis was added to the list of recommended reportable diseases beginning in 1995 because of the naturally occurring, endemic risk. Reporting of cases to the United States Centers for Disease Control (CDC) is recommended for the endemic states. The recommendation was applied to the endemic states, with reporting in the other states being left to a voluntary basis. As documented by Chaturvedi et al. (2000), coccidioidomycosis cases are seen in patients who reside in nonendemic states following acquisition in the endemic state and subsequent presentation elsewhere. Their review of hospital discharge data in New York State found a mean of 30 discharges per year between 1992 and 1997. Strain typing of the isolates, where available, indicated that the strains originated in the endemic South-west (Chaturvedi et al. 2000). The publication stands as an example of the need for increased awareness for this infection, and for vigilance in laboratory safety for filamentous fungi recovered in the clinical laboratory. Also, it stands as evidence for encouraging reporting of the disease in nonendemic states as well as endemic states to enable the ability to detect group exposure to the organism occurring through natural or unnatural means. A report of brucellosis, one of the diseases connected to the Select Agent list, to the CDC aroused suspicion of the source and circumstances of the infection that occurred recently in New York City and provided the opportunity to safeguard the public health (CDC 1999).

Coccidioidomycosis is also a threat to the US military. It can be considered an endemic threat as exemplified in the title of the following publication title –‘Coccidioidomycosis: a persistent threat to deployed populations’ (Rush et al. 1993). It was estimated that during the period of 1983–7 there were 115 000 Air Force personnel on duty in endemic regions, that there were 126 coccidioidomycosis admissions in AF hospitals and that there were 20 admissions per year per 100 000 active duty AF personnel in Arizona bases. The threat can be particularly insidious when immunologically naïve troops move into the endemic regions of the US for training and then are deployed to distant sites where the disease can manifest after leaving the endemic area, and may not be readily considered in the differential diagnosis.

The report, ‘Coccidioidomycosis among Military Personnel in Southern California’ provided a useful immunological natural history study in this regard (Hooper et al. 1980). Of 1438 troops studied, 21% were skin test positive on initial testing. Skin test conversion rates were followed from this baseline; the conversion rate was 25·4% over six to eight months. These well-characterized military studies are excellent examples of what can happen when any immunologically naïve population moves into the endemic area.

In Arizona, one of the fastest growing age groups with increased incidence of skin test reactivity to coccidioidin is the over 65 years of age group, presumably because of the influx of these individuals to retirement communities from communities outside of the endemic area (CDC 1996). One might say that no one group is ‘immune’ without having been immunized either by subclinical infection, or perhaps some day by a vaccine for coccidioidomycosis.

Large-scale genome sequencing technology has brought a wealth of opportunity to biological studies. The NIH/NIAID has responded to the opportunity to apply genome sequencing and genomics to the mission of improving human health, and to key areas such as prevention, diagnosis and treatment of infection. Large-scale genome sequencing projects for pathogens were coordinated, beginning with the announcement of new policy in 2000 for FY 2001 for this purpose. The policy involved specifying a priority list of organisms for receipt of applications to be considered for the cooperative agreement funding (a grant) mechanism allowing up to three million dollars over two years for the award. The NIAID has sponsored whole genome or chromosome sequencing for more than 40 bacteria and higher organisms through the end of 2000 using R01 and U01 funding mechanisms. The first priority list under the new policy included the following eukaryotic organisms for FY 2001: Anopheles gambiae, Aspergillus fumigatus, Cryptococcus neoformans, Cryptosporidium parvum and Schistosoma mansoni. For FY 2002, the eligibility list includes Coccidioides immitis as well as Histoplasma capsulatum (http://www.niaid.nih.gov/dmid/genomes/priorities.htm).

The availability of large scale genomic information on C. immitis should provide major opportunities to the biomedical community in pursuit of better means of diagnosis or detection, prevention and treatment. Therefore, inclusion of C. immitis on the NIAID list of priority organisms for eligibility for whole genome sequencing is an important step in enabling the research community and the public health good. Given the potential gravity of disease, the capability for subclinical or quiescent infections to relapse or reactivate when immunosuppression results, and given the low index of suspicion of infection, especially for presentation of disease outside of the endemic regions, or outside of natural circumstances, preventive measures seem especially appealing to pursue in today’s world.

References

  1. Top of page
  2. 1. SUMMARY
  3. 2. INTRODUCTION
  4. 3. INFECTION WITH COCCIDIOIDES IMMITIS
  5. 4. TREATMENT OF COCCIDIOIDOMYCOSIS
  6. 5. INCIDENCE OF COCCIDIOIDOMYCOSIS
  7. 6. DEVELOPMENT OF VACCINE
  8. 7. SELECT AGENT RULE
  9. References
  • 1
    CDC (1993) Coccidioidomycosis – United States. 1991–1992. MMWR 42 (2),2124.
  • 2
    CDC (1994) Update: Coccidioidomycosis – California, 1991–1993. MMWR 43 (23),421423.
  • 3
    CDC (1996) Coccidioidomycosis – Arizona, 1990–1995. MMWR 45 (49),10691073.
  • 4
    CDC (1999) Suspected brucellosis case prompts investigation of possible bioterrorism-related activity – New Hampshire and Massachusetts, 1999. MMWR 49 (23),509512.
  • 5
    Chaturvedi, V., Ramanik, R., Gromadzki, S., Rodeghier, B., Chang, H., Morse, D. (2000) Coccidioidomycosis in New York State. Emerging Infectious Diseases 6 , 2529.
  • 6
    Department of Health and Human Services (1993) In: Biosafety in Microbiological and Biomedical Laboratories, 3rd edn, May, 1993, US DHHS, Public Health Service, HHS Publication No (CDC) 93–8395. p. 79. US Government Printing Office.
  • 7
    Department of Health and Human Services (1996) Additional requirements for facilities transferring or receiving select agents. 42 CFR Part 72 Federal Register 61 (207).
  • 8
    Drutz, D.J. & Huppert, M. (1983) Coccidioidomycosis: factors affecting the host–parasite interaction. Journal of Infectious Diseases 147 (3),372390.
  • 9
    Galgiani, J.N. (1993) Coccidioidomycosis. Western Journal of Medicine 159 , 153171.
  • 10
    Hooper, R., Curley, R., Poppell, G., Husted, S., Shillaci, R. (1980) Coccidioidomycosis among Military Personnel in Southern California. Military Medicine 145 (9),620623.
  • 11
    Kirkland, T.N. & Fierer, J. (1996) Coccidioidomycosis: a reemerging infectious disease. Emerging Infectious Diseases 2 (3),192199.
  • 12
    Labadie, E.L. & Hamilton, R.H. (1986) Survival improvement in coccidioidal meningitis by high-dose intrathecal amphotericin B. Archives of Internal Medicine 46 (10),20138.
  • 13
    Pappagianis, D. (1994) Marked increase in cases of coccidioidomycosis in California: 1991, 1992, and 1993. Clinical Infectious Diseases 19 (Suppl. 1),S14S18.
  • 14
    Pappagianis, D. and The Valley Fever Vaccine Study Group. (1993) Evaluation of the protective efficacy of the killed Coccidioides immitis spherule vaccine in humans. American Review of Respiratory Diseases 148 (3),656660.
  • 15
    Rippon, J.W. (1988) Medical Mycology: the Pathogenic Fungi and the Pathogenic Actinomycetes 3rd edn. Philadelphia: Saunders.
  • 16
    Rush, W.L., Dooley, D.P., Blatt, S.P., Drehner, D.M. (1993) Coccidioidomycosis: a persistent threat to deployed populations. Aviation, Space and Environmental Medicine 64 , 653657.