Public and Medical Misinformation on Valley Fever By David Filip Presented 4/23/2014

1. Public and Medical Misinformation on Valley Fever By David Filip Presented 4/23/2014

3. Although a discussion of misinformation may sound controversial, this presentation is founded on information in peer reviewed medical journals and historical accounts. The only controversy should be the fact that this information is not already common knowledge.

4. Conventional Wisdom

5. Sometimes the conventional wisdom on Valley Fever is not only baseless but is misinformation that whitewashes the truth and would lead people astray unless they chose to dig into the research themselves

6. Consider the Emperor's New Clothes

7. A frightening example of misinformation: "Doctor [name withheld] says washing your hands is the best way to prevent valley fever." Valley Fever cases on the upswing locally KOB Albuquerque, NM April 1, 2013

8. Common Valley Fever "Sound Bites"How true are they? Infected people have a lifelong immunity Most people won't know they have the disease It is a small problem It is important to focus on specific risk factors Masks can protect people from Valley Fever It is only a local problem

9. I will deconstruct each of these statements to show how even accurate statements could be misinterpreted and misused to the detriment of public health, as well as to show ways to share the whole and useful truth quickly and effectively.

10. Once infected, a person with Valley Fever will have lifelong immunity – that is said everywhere from doctors offices to medical journals to the evening news. It is the basis of a vaccine It is the reason much of the Southwest's population is not debilitated Based on the peer reviewed literature, it is not always true as a blanket statement. In fact, in some cases it has been proven false. Do infected people have a lifelong immunity?

11. "Relapse rates in prospective studies of the [azole drugs for Valley Fever] have ranged from 16% to 67%, with a reasonable estimate of 25%-35% after therapy.” “The overall response to treatment with azoles appears somewhat less than that to treatment with amphotericin B; relapses occur in about one-third of patients treated with azoles.” Einstein HE, Johnson RH. Coccidioidomycosis: new aspects of epidemiology and therapy. Clin Infect Dis 1993;16:349-56. Do infected people have a lifelong immunity?

12. In a review of 223 cases across a decade, 24% with dissemination relapsed and 71% with Central Nervous System involvement such as meningitis relapsed. Even “following apparently successful treatment” patients relapse one third of the time. Crum NF, Lederman ER, Stafford CM, Parrish JS, Wallace MR. Coccidioidomycosis: A Descriptive Survey of a Reemerging Disease. Clinical Characteristics and Current Controversies. Medicine. 83(3):149-175, May 2004. Do infected people have a lifelong immunity?

13. “Relapse remains one of the most significant problems in the treatment of coccidioidomycosis.” Oldfield EC 3rd, Bone WD, Martin CR, Gray GC, Olson P, Schillaci RF. Prediction of relapse after treatment of coccidioidomycosis. Clin Infect Dis. 1997 Nov;25(5):1205-10. Do infected people have a lifelong immunity?

14. People contacting ValleyFeverSurvivor.com often tell us that their doctors won't treat them as symptoms return and the doctors often refuse to test for Valley Fever to begin with. However, “rising titers warrant the administration of therapy, even in the absence of evident disease, since relapse is likely.” Stevens DA. Adequacy of therapy for coccidioidomycosis. Clin Infect Dis 1997 Nov;25(5):1211-2. Do infected people have a lifelong immunity?

15. "Coccidioidomycosis is a systemic fungal infection and is frequently refractory to treatment. Unfortunately, conventional antifungal therapy is associated with therapeutic failures, relapses, and toxicity." Gonzalez GM, Tijerina R, Najvar LK, Bocanegra R, Luther M, Rinaldi MG, Graybill JR. Correlation between antifungal susceptibilities of Coccidioides immitis in vitro and antifungal treatment with caspofungin in a mouse model. Antimicrob Agents Chemother. 2001 Jun;45(6):1854-9. Do infected people have a lifelong immunity?

16. “The disease may recur years after exposure or treatment.” Caraway NP, Fanning CV, Stewart JM, Tarrand JJ, Weber KL. Coccidioidomycosis osteomyelitis masquerading as a bone tumor. A report of 2 cases. Acta Cytol. 2003 Sep-Oct;47(5):777-82. “Reactivation of a previously disseminated coccidioidal infection, even after apparently successful antifungal therapy, is not uncommon.” Pappagianis D. Coccidioides immitis. In Collier L, Balows A, Sussman M, Ajello L, Hay RJ, eds. 9th ed. Topley and Wilson's microbiology and microbial infections, Vol. 4, Medical Mycology. London: Arnold 1998. p357-371. Do infected people have a lifelong immunity?

17. Even in those who are not treated, Valley Fever’s lung lesions are known to expand, sometimes years later. Coccidioidomycosis. MedlinePlus Medical Encyclopedia. <http://www.nlm.nih.gov/medlineplus/ency/article/001322.htm> This makes it important for Valley Fever patients to keep track of their x-rays of lung nodules, since they have frequently been mistaken as cancer. Arizona Respiratory Center. What you Should Know About Valley Fever (Coccidioidomycosis). University of Arizona Health Sciences Center <http://www.respiratory.arizona.edu/patient-info/adults/valley-fever-a.htm> Do infected people have a lifelong immunity?

18. “Despite the prevalent belief that primary attack of coccidioidomycosis confers a lasting immunity, there are many cases which do not follow this simple concept. Examples have been presented illustrating that the disease can resolve and then reappear; that residual nodules and cavities can reactivate; that surgery and debilitating conditions can produce reactivations; and that late disseminations can occur. In addition, exogenous reinfection can also occur by both pulmonary and extrapulmonary routes.” Salkin D. Clinical examples of reinfection in coccidioidomycosis. Am Rev Respir Dis. 1967 Apr;95(4):603-11. Do infected people have a lifelong immunity?

19. Testimony about Valley Fever to the Arizona State Senate committee on health "pointed out the problems with current therapy, noting that less than 70% of patients respond to therapy. However, when therapy is stopped, relapses occur." Galgiani, JN. Minutes of the Arizona State Senate Committee on Health. Phoenix, AZ 4 Feb 2002. http://www.azleg.state.az.us/FormatDocument.asp?inDoc=/legtext/46leg/1R/comm_min/Senate/0213+HEA%2EDOC.htm Accessed 8/01/2003. Do infected people have a lifelong immunity?

20. “Unfortunately, the rates of failure and relapse after treatment of chronic pulmonary or disseminated Coccidioidomycosis are disappointingly high.” Laniado-Laborín R. Cost-benefit analysis of treating acute coccidioidal pneumonia with azole drugs. In: Proceedings of the Forty-Fifth Annual Coccidioidomycosis Study Group Meeting. March 31, 2001. The University of Arizona. Tucson, Arizona. Do infected people have a lifelong immunity?

21. There are no major long term studies specifically following people with dormant Valley Fever to observe how they are struck by it later in life. There are many studies and case reports following patients who relapsed severely after seemingly defeating the disease with medication. Do infected people have a lifelong immunity?

22. Documentation has also proven that patients’ infections relapsed (or activated for the first time) years after leaving the endemic zones where they contracted Valley Fever. Antony SJ, Jurczyk P, Brumble L. Successful use of combination antifungal therapy in the treatment of coccidioides meningitis. J Natl Med Assoc. 2006 Jun;98(6):940-2. Bellin HJ, Bhagavan BS. Coccidioidomycosis of the prostate gland. Report of a case and review of the literature. Arch Pathol. 1973 Aug;96(2):114-7. Catanzaro A, Cloud GA, Stevens DA, Levine BE, Williams PL, Johnson RH, Rendon A, Mirels LF, Lutz JE, Holloway M, Galgiani JN. Safety, tolerance, and efficacy of posaconazole therapy in patients with nonmeningeal disseminated or chronic pulmonary coccidioidomycosis. Clin Infect Dis. 2007 Sep 1;45(5):562-8. Epub 2007 Jul 23. Cole GT, Xue JM, Okeke CN, Tarcha EJ, Basrur V, Schaller RA, Herr RA, Yu JJ, Hung CY. A vaccine against coccidioidomycosis is justified and attainable. Med Mycol. 2004 Jun;42(3):189-216. Crum NF, Lederman ER, Stafford CM, Parrish JS, Wallace MR. Coccidioidomycosis: A Descriptive Survey of a Reemerging Disease. Clinical Characteristics and Current Controversies. Medicine (Baltimore). 2004 May;83(3):149-175. Johnson RH, Einstein HE. Forty-five years of disseminated coccidioidomycosis. In: Proceedings of the Forty-Sixth Annual Coccidioidomycosis Study Group Meeting. March 31, 2001. The University of Arizona. April 6, 2002. Davis, California. VFCE. Oldfield EC 3rd, Bone WD, Martin CR, Gray GC, Olson P, Schillaci RF. Prediction of relapse after treatment of coccidioidomycosis. Clin Infect Dis. 1997 Nov;25(5):1205-10.

23. When he was infected in 1957 he experienced pneumonia and appeared to recover. In 1958 he had a reactivation of his Valley Fever that required the removal of a testicle and other parts of his genitourinary tract. Again the Valley Fever went dormant, until it reactivated over four decades later as meningitis in 2002 to kill him. Even when an infected person does not look or feel sick, reactivation is always a dangerous lingering possibility with this disease. Johnson RH, Einstein HE. Forty-five years of disseminated coccidioidomycosis. In: Proceedings of the Forty-Sixth Annual Coccidioidomycosis Study Group Meeting. March 31, 2001. The University of Arizona. April 6, 2002. Davis, California. A Severe Reactivation

24. Lab accidents and animal data proving that reinfection is possible Salkin D. Clinical examples of reinfection in coccidioidomycosis. Ajello L, ed. Coccidioidomycosis. Papers from the second symposium on coccidioidomycosis. Tucson: University of Arizona Press, 1967: 11-18. Shubitz LF, Peng T, Perrill R, Simons J, Orsborn K, Galgiani JN. Protection of mice against Coccidioides immitis intranasal infection by vaccination with recombinant antigen 2/PRA. Infect Immun. 2002 Jun;70(6):3287-9. Do infected people have a lifelong immunity?

25. Fifteen trillion Coccidioides arthroconidia can fit into a cubic inch. Valley Fever Center for Excellence. Frequently Asked Questions. http://www.vfce.arizona.edu/FAQ.htm It is impossible to predict when any breath of air in an endemic area might contain enough spores to demolish an infected person’s immune resistance. Reinfection with Valley Fever may be something commonly regarded by some as impossible, but it is also a proven fact Do infected people have a lifelong immunity?

26. Reinfections and Reactivations Do infected people have a lifelong immunity?

27. Dose dependence: The question is not whether experimental vaccines are protective, but at what dose are they protective? Concerns of reinfection and reactivation could follow a similar line of thought. Do infected people have a lifelong immunity?

28. It has been shown that dormant Coccidioides in some patients activated as “lesions that occurred after various forms of trauma, including those ensuing on medical-surgical procedures. What factors may contribute to such local proliferation of C. immitis are not yet explained.” Pappagianis D. The phenomenon of locus minoris resistentiae in coccidioidomycosis. In: Einstein HE, Catanzaro A, eds. Coccidioidomycosis. Proceedings of the 4th International Conference on Coccidioidomycosis. Washington, DC. National Foundation for Infectious Diseases; 1985: 319-329. Reactivations and Locus Minoris Resistentiae (LMR)

29. It has also been reported that other active bacterial and viral diseases can lead to the reactivation of dormant Valley Fever. Cole GT, Xue JM, Okeke CN, Tarcha EJ, Basrur V, Schaller RA, Herr RA, Yu JJ, Hung CY. A vaccine against coccidioidomycosis is justified and attainable. Med Mycol. 2004 Jun;42(3):189-216. Reactivations and Locus Minoris Resistentiae (LMR)

30. Reactivations like these “indicate that relatively silent dissemination from a primary pulmonary focus does occur. However, many of the present episodes of peripheral coccidioidal lesions could not be associated with a recent respiratory infection. Thus, C. immitis may have been present in the blood at the time of injury and settled in the injured site, or it may have previously been deposited via the circulation in the tissue which was later injured, setting the stage for fungal replication and development of a lesion.” Pappagianis D. The phenomenon of locus minoris resistentiae in coccidioidomycosis. In: Einstein HE, Catanzaro A, eds. Coccidioidomycosis. Proceedings of the 4th International Conference on Coccidioidomycosis. Washington, DC. National Foundation for Infectious Diseases; 1985: 319-329. Reactivations and Locus Minoris Resistentiae (LMR)

31. Dr. Demosthenes Pappagianis was the first to describe this phenomenon in Valley Fever with the term “locus minoris resistentiae.” LMR is based on an old laboratory term meaning “lessened resistance at a local area.” Reactivations and Locus Minoris Resistentiae (LMR)

32. One example was a man who was struck in the shoulder by a tree branch while riding on a tractor, and had Valley Fever activate in his shoulder. Another was a dock worker outside the endemic area who had a heavy weight fall on his foot, and soon had his latent Valley Fever activate in that foot. Pappagianis, D. Personal Communication. Reactivations and Locus Minoris Resistentiae (LMR)

33. LMR has also been known to occur in other diseases, like bacterial osteomyelitis and syphilis. Pappagianis D. The phenomenon of locus minoris resistentiae in coccidioidomycosis. In: Einstein HE, Catanzaro A, eds. Coccidioidomycosis. Proceedings of the 4th International Conference on Coccidioidomycosis. Washington, DC. National Foundation for Infectious Diseases; 1985: 319-329. Reactivations and Locus Minoris Resistentiae (LMR)

34. More Valley Fever examples include an infection in the leg, Pappagianis D, Welland F, Jordan G. Backache and Ulcer of Calf in a human. In: Ajello L, ed. Coccidioidomycosis. Papers from the second symposium on coccidioidomycosis. Tucson: University of Arizona Press, 1967: 19-22. a disseminated infection of the epididymis that apparently spread to the testicle after a blunt trauma, Fiese MJ. Coccidioidomycosis. Springfield, Charles C. Thomas, 1958: Ch8 Pathology and pathogenesis of Coccidioidomycosis. P104-126. and the upper chest where a man was punched in a Judo class Caraway NP, Fanning CV, Stewart JM, Tarrand JJ, Weber KL. Coccidioidomycosis osteomyelitis masquerading as a bone tumor. A report of 2 cases. Acta Cytol. 2003 Sep-Oct;47(5):777-82. Reactivations and Locus Minoris Resistentiae (LMR)

35. LMR may also apply in the cases of children who fell and subsequently developed osteomyelitis from Valley Fever at the site of their injuries. Iger M. Coccidioidal osteomyelitis. In: Ajello L, ed. Coccidioidomycosis: Current clinical and diagnostic status. Miami: Symposia Specialists; 1977: 177-190. Bried JM, Speer DP, Shehab ZM. Coccidioides immitis osteomyelitis in a 12-month-old child. J Pediatr Orthop 1987 May-Jun;7(3):328-30. “Several anatomical sites have been involved - upper and lower extremities, face, thorax, and an internal surgical site.” Pappagianis D. The phenomenon of locus minoris resistentiae in coccidioidomycosis. In: Einstein HE, Catanzaro A, eds. Coccidioidomycosis. Proceedings of the 4th International Conference on Coccidioidomycosis. Washington, DC. National Foundation for Infectious Diseases; 1985: 319-329. Reactivations and Locus Minoris Resistentiae (LMR)

36. Reactivations of “surgical cases are of special interest because operative trauma and post-operative pulmonary mechanical changes form an extraneous force which can upset a tenuous immunity.” Salkin D. Clinical examples of reinfection in coccidioidomycosis. In: Ajello L, ed. Coccidioidomycosis. Papers from the second symposium on coccidioidomycosis. Tucson: University of Arizona Press, 1967: 11-18. Reactivations and Locus Minoris Resistentiae (LMR)

37. Having Valley Fever's symptoms once does NOT guarantee total protection for the future. For the sake of accuracy and honesty in communications, "immune resistance" is better than saying "total immunity" because there are many ways that this resistance can be overcome. Do infected people have a lifelong immunity?

38. Many patients have mentioned their doctor told them once they had a case of Valley Fever that they would never suffer symptoms again, and any sickness they experienced was from something else. This caused years of improper medical care until future doctors ultimately were willing to listen and work on the real problem. The difference between "immune resistance" and "total immunity" must be made clearer in the future for the medical community and lay audience alike. Do infected people have a lifelong immunity?

39. "Most people won't know they have Valley Fever" Is this true? The estimate that 60% of cases would be asymptomatic came from military studies during World War II Smith CE, Beard RR. Varieties of coccidioidal infection in relation to the epidemiology and control of diseases. Am J Public Health 1946;36:1394-402.

40. In today's population, the more important question is whether we should assume so many infections will not have symptoms.

41. According to the Arthritis Foundation, 50 million Americans have arthritis. This is 1/6th of the population. How much of this is from fungal disease in general or Valley Fever in particular? The data is incomplete.

42. How accurate has Valley Fever testing been? The blood tests are among the most commonly used form of diagnosis. False positives had been noted under the particular circumstance of an EIA test with positive IgM antibodies but negative IgG antibodies. Kuberski T, Herrig J, Pappagianis D. False-positive IgM serology in coccidioidomycosis. J Clin Microbiol. 2010 Jun;48(6):2047-9. doi: 10.1128/JCM.01843-09. Epub 2010 Mar 31. Blair JE, Currier JT. Significance of isolated positive IgM serologic results by enzyme immunoassay for coccidioidomycosis. Mycopathologia. 2008 Aug;166(2):77-82. doi: 10.1007/s11046-008-9129-9. Epub 2008 Jun 4.

43. False negatives are a greater concern among the variety of blood tests for valley fever. In a 2006 study that evaluated tests in people already known to have Valley Fever, how often were blood tests accurate? • EIA tests were positive 82% of the time • Immunodiffusion tests: 71% of the time • Complement fixation: 56% of the time Pollage CR, et al. Revisiting the sensitivity of serologic testing in culture positive coccidioidomycosis. Presented at the 106th Annual Meeting of the American Society of Microbiology. Orlando, FL. 2006. Cited in: Saubolle MA. Laboratory aspects in the diagnosis of coccidioidomycosis. Ann N Y Acad Sci. 2007 Sep;1111:301-14. Epub 2007 Mar 15.

44. In a case report, the patient had a lumbar puncture to test for cocci, but it was not found there. However, a blood test had a colossally high titer of 1:512. This and similar cases illustrate the need for ongoing testing, repeated testing and often more than one type of testing. Gibbs BT, Neff RT. A 22-year-old Army private with chest pain and weight loss. Mil Med. 2004 Feb;169(2):157-60.

45. One study was a specific attempt to find Valley Fever in Arizona by testing hospitalized patients with community acquired pneumonia. It led to a discovery that 29% were Valley Fever infections and not the expected influenza or bacterial pneumonia cases. Valdivia L, Nix D, Wright M, Lindberg E, Fagan T, Lieberman D, Stoffer T, Ampel NM, Galgiani JN. Coccidioidomycosis as a common cause of community-acquired pneumonia. Emerg Infect Dis. 2006 Jun;12(6):958-62.

46. The rate of testing for Valley Fever ranges from 13% to as little as 2% of pneumonia cases, so the question of a subclinical case may be up to the doctors' willingness to consider Valley Fever at all. Chang DC, Anderson S, Wannemuehler K, Engelthaler DM, Erhart L, Sunenshine RH, Burwell LA, Park BJ. Testing for coccidioidomycosis among patients with community-acquired pneumonia. Emerg Infect Dis. 2008 Jul;14(7):1053-9. doi: 10.3201/eid1407.070832.

47. Peer review should be an answer to the release of bad data and bad decisions. It could get every doctor and epidemiologist on the same page with all the right answers so they can share perfection with the media...in theory.

48. Benefits of peer review are... 1) It filters out the generally uneducated 2) It sets a standard of communication 3) Professionals familiar with the topic can point to holes in a theory 4) Peer pressure for accuracy

49. In the general public, there seems to be a horrible misconception that Valley Fever is just like a cold, or that if it WERE serious, it would already be under control. Questionnaire respondents have often said they had no idea how serious the disease was, and point to the estimates released to the news about the overall scope of the epidemic. "Valley Fever is not a small problem"

50. Different journal articles from the 1950's to the 2000's repeatedly estimated 100,000 people in the USA were infected each year.