Basics of Pulmonary Valley Fever

Coccidioides (from now on, called Cocci) is an endemic fungi that exists in two forms, yeast and mold, that is endemic to the southeastern United States (1). It is related to both Histoplasma and Blastomyces with two species known to infect humans. C. immitis and C. posadasii. Arthroconidia can be transported in soil or fomites, with one classic example being infection following a severe dust storm. In these endemic areas, prevalence can be higher than expected. For instance, one study of over 2000 community acquired pneumonia patients enrolled in the Kaiser Permanente Southern California system (KPSC) found that 18% (377) were positive for coccidiomyocosis by any test (2). Moreover, being female (aOR 0.6) was associated with lower odds of testing positive, however those of Filipino ethnicity (aOR 3.56), non-Hispanic blacks (aOR 2.78), and Hispanics (aOR) were more likely to test positive. In a similar study evaluating ambulatory patients with CAP in Maricopa County, incidence of pulmonary coccidioides increased from  42 per 100,000 in 1999 to 77 per 100,000 in 2004 (3). Multivariate analysis found that adult patients (aOR 5.3) and those who had reported a rash (aOR 21.1), chest pain (aOR 3.9) or symptoms for >14 days (aOR 4.1) were more likely to be tested for cocci. In a cohort of 56 outpatients from Tucson, Arizona the attack rate for pulmonary coccidioides was determined to be 29%, with the only difference in symptoms between those with valley fever and those without it being the presence of myalgias in the former group (5):

The frequency of cocci in another cohort from Phoenix was 17% (5). 

Acute Symptoms:

Inhalation of a single conidia is enough to cause symptoms in those exposed to cocci. I’ll be talking about those who present with typical pneumonia, namely those who are not immunosuppressed. Further, I’ll be talking about the initial presentation rather than reactivation (1). Roughly 2/3rds of patients who are exposed will not have any symptoms, and many of those who do tend to have symptoms indistinguishable from community acquired pneumonia. One of the first case series described 75 patients who had returned from a trip in Antelope Plain, California (6). The incubation period was 14-21 days, with symptoms consisting of thoracic pain (88%), cough (88%), chills and fever (66%), sore throat (37%), and rash (19%). One case series describes an outbreak of coccidioidomycosis in a 126-member church group who had returned from Tecate, Mexico, where members assisted with construction projects at an orphanage (7). The attack rate in that cohort was 17%, with 20 out of 21 patients who had positive serology having some sort of symptoms, of which fever, headache, chest pain, body aches, cough, and fatigue were the most common. 

A 24-week prospective study evaluated 36 patients with mild to moderate pulmonary coccidioidomycosis (8). The most common symptoms overall were fatigue (100%), fever (86%), chills (89%), cough (94%), night sweats (91%), and headache (81%). Moreover, time to improvement between those who got antifungals and those who didn’t was roughly the same:

Skin manifestations are also relatively common. One review highlights a 4 year period where 1351 patients were diagnosed with coccidioidal infections. Of these, only 62 were found to have erythema nodosum (9). In one case series, 2 patients presented with both pulmonary coccidioidomycosis along with diffuse plaques consistent with a diagnosis of Sweet’s syndrome (10):

Diagnosis:

Antibodies. The crux of diagnosing cocci is antibodies, or at least the body’s ability to make them. Culturing cocci in the lab is hazardous (not the sample collecting but rather the growth part of it, 1), and also a bit labor intensive so we count on surrogates to make a diagnosis. However, considering that it takes some time for the body to make these antibodies, repeat testing in a few weeks is necessary for confirming the diagnosis. There are 2 antibodies you’ll hear about when it comes to testing: tube precipitin and complement-fixing antibodies. They describe how they work: tube precipitin detects the formation of a “precipitin button” that forms at the bottom of the test tube after overnight incubation (1). IgM is the one that is most avid at formin immune precipitins, so this test is for IgM. Complement fixation, on the other hand, uses IgG to kick-start the complement fixation cascade. Patient’s serum which has cocci antigen has antibody-coated RBCs added to them; using IgG, complement fixation is started and thus, the test turns positive (1). One review highlights the complexity of serological studies for cocci (11). The host response to infection follows a very predictive course: for instance, a delayed cutaneous hypersensitivity occurs within 3 days to 3 weeks after onset of symptoms, which is then followed by the precipitin testing turning positive as the disease progresses:

In other words, precipitins appear more rapidly than CF antibodies. The one advantage of CF is its ability to predict severity. Only 1% of non-disseminated disease had CF antibodies greater than 1:32, with the critical threshold being anywhere from 1:16 to 1:32:

One early study evaluated the pattern of over 39,000 preciptin and complement-fixation tests. A few patterns were established here (11). First, complement fixation tended to be reactive mostly in disseminated disease with only 2% of cases of disseminated infection being diagnosed with precipitins. Indeed, precipitin  was the only antigen detected in non-disseminated infection in 44% of cases:

Precipitin positivity peaked at around the third to fourth week of illness, with subsequent decline to only 10% positivity by the fifth month: 

A review notes that during the first week of illness, 53% of patients with primary non disseminated coccidioidomycosis had detectable antibodies by TP, which increased to 91% at weeks 2 to 3 of illness with the sensitivity being greater in the IDTP/LA testing (12). At 7 months after presentation, only 7% of patients were positive by TP reactivity, with the bulk (48%) of those who were positive having disseminated disease.  Complement fixation tends to pick up the late antigen (i.e. IgG), and its quantitative nature allows one to gauge the severity of disease. For instance, CF titers greater than 16 should tip off someone the possibility of disseminated disease. As can be seen below, the higher titers tended to be correlated with more disseminated disease:

Complement fixation is a common modality used in most of the country, however it is generally a send out and can take a while to come back. Other antibody assays have been employed. One study compared the utility of the Meridian Premier Coccidioides EIA in 226 specimens, including 66 CSF specimens (13). When compared to complement fixation, the overall specificity, sensitivity, PPV and NPV were 98%, 100%, 96%, and 100%, respectively. It should be noted these data was on specimens obtained from an endemic area, meaning the PPV and NPV may not be applicable to patients outside of said areas:

Two enzyme immunoassay for cocci, including the aforementioned Meridian assay, were evaluated in a group of 534 sera from people outside of an endemic region and 1218 from an area of endemicity (14). These were compared to both complement fixation and tube preciptin antigen, with IgM being positive in those who were outside of an era of endemicity at a similar rate to those of an endemic area:

Notably, IgG was positive at a higher rate in the sera from the endemic region, reflecting possible cross-reactivity for IgM. In another study, ELISA was compared with CF and immunodiffusion (15). Sensitivity, specificity, PPV, and NPV were 92.6%, 98.3%, 98% and 93.7%, respectively. The Premier EIA was also compared in a cohort of 409 specimens of which 47 had confirmed coccidioides (16). Overall, when compared to CF, the EIA correlated with CF detecting all 47 when combining both IgM and IgG:

Notably, there was some cross reactivity between the EIA and other endemic fungi. More interestingly, 36/47 had reactive IgM suggesting that to confirm the diagnosis using the Premier EIA one needs to perform convalescent serologies. One study evaluated the utility of IgM-only EIA relative to symptoms and found that 90% of those with symptoms had confirmed, highly probable, or probably coccidioidal illness (17).

Have other modalities for diagnostics been looked at? Sure. One retrospective study evaluated the utility of Histoplasma antigen testing in 19 patients with coccidioides (18). 17 of these had an underlying condition such as HIV or solid-organ transplant. Antigen was detected in the urine in 79% of those who had an acute case. 188 patient sera evaluated the role of BD glucan (19). 47 of these had acute coccidioidomycosis, of which 53.2% had a positive BD glucan (>31). 83% of cases of disseminated or meningeal cocci had BG values >31, however these correlated poorly with serum CF antibody titers. In other words, BD glucan sensitivity correlated with disease severity to a certain extent i.e. it had a greater sensitivity in hospitalized patients:

Moreover, in a small study of 12 samples that were positive for the Cocci antigen, 92% had BD glucan values > 80 pg/mL (20). So perhaps BD glucan can be used to track disease progress, although CF titers seem to fulfill that role at the moment. . 

More specific assays have been studied as well. PCR has been compared to fungal culture in a retrospective cohort of 100 BAL specimens (21). Here, the sensitivity and specificity, respectively were 100 and 95%. Similar findings were obtained in a prospective study of 232 specimens, with sensitivity and specificity being 100 and 99%, respectively. A prospective observational study compared the lateral flow assay with the standard EIA in a group of 402 patients. Of the 65 subjects who were positive by EIA, only 31% had a positive LFA. 305 patients who were EIA negative, of which 91.8% were also negative by LFA (22). 

To highlight the modalities, one recent review published in OFID (23) has a nice table summarizing all diagnostic methods:

References:

1. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Ninth edition. Philadelphia, PA: Elsevier, 2020. 
2. Tartof SY, Benedict K, Xie F, Rieg GK, Yu KC, Contreras R, Truong J, Fong K, Tseng HF, Jacobsen SJ, Mody RK. Testing for Coccidioidomycosis among Community-Acquired Pneumonia Patients, Southern California, USA1. Emerg Infect Dis. 2018 Apr;24(4):779-781. doi: 10.3201/eid2404.161568. PMID: 29553315; PMCID: PMC5875278.
3. 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. PMID: 18598625; PMCID: PMC2600364.
4. 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. doi: 10.3201/eid1206.060028. Erratum in: Emerg Infect Dis. 2006 Aug;12(8):1307. PMID: 16707052; PMCID: PMC3373055.
   
5. Kim MM, Blair JE, Carey EJ, Wu Q, Smilack JD. Coccidioidal pneumonia, Phoenix, Arizona, USA, 2000-2004. Emerg Infect Dis. 2009 Mar;15(3):397-401. doi: 10.3201/eid1563.081007. PMID: 19239751; PMCID: PMC2681119.
6. GOLDSTEIN DM, McDONALD JB. PRIMARY PULMONARY COCCIDIOIDOMYCOSIS: FOLLOW-UP OF 75 CASES, WITH 10 MORE CASES FROM A NEW ENDEMIC AREA. JAMA. 1944;124(9):557–561. doi:10.1001/jama.1944.02850090013004
7. 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 Jan;30(1):61-4. doi: 10.1086/313602. PMID: 10619734.
8. Blair JE, Chang YH, Cheng MR, Vaszar LT, Vikram HR, Orenstein R, Kusne S, Ho S, Seville MT, Parish JM. Characteristics of patients with mild to moderate primary pulmonary coccidioidomycosis. Emerg Infect Dis. 2014 Jun;20(6):983-90. doi: 10.3201/eid2006.131842. PMID: 24865953; PMCID: PMC4036774.
9. SMITH CE, BEARD RR, et al. Varieties of coccidioidal infection in relation to the epidemiology and control of the diseases. Am J Public Health Nations Health. 1946 Dec;36(12):1394-1402. doi: 10.2105/ajph.36.12.1394. PMID: 20278046; PMCID: PMC1624510.
10. DiCaudo DJ, Ortiz KJ, Mengden SJ, Lim KK. Sweet syndrome (acute febrile neutrophilic dermatosis) associated with pulmonary coccidioidomycosis. Arch Dermatol. 2005 Jul;141(7):881-4. doi: 10.1001/archderm.141.7.881. PMID: 16027305.
11. SMITH CE, SAITO MT, SIMONS SA. Pattern of 39,500 serologic tests in coccidioidomycosis. J Am Med Assoc. 1956 Feb 18;160(7):546-52. doi: 10.1001/jama.1956.02960420026008. PMID: 13286095.
12. Pappagianis D, Zimmer BL. Serology of coccidioidomycosis. Clin Microbiol Rev. 1990 Jul;3(3):247-68. doi: 10.1128/CMR.3.3.247. PMID: 2200605; PMCID: PMC358158.
13. Zartarian M, Peterson EM, de la Maza LM. Detection of antibodies to Coccidioides immitis by enzyme immunoassay. Am J Clin Pathol. 1997 Feb;107(2):148-53. doi: 10.1093/ajcp/107.2.148. PMID: 9024063.
14. Lindsley MD, Ahn Y, McCotter O, Gade L, Hurst SF, Brandt ME, Park BJ, Litvintseva AP. Evaluation of the Specificity of Two Enzyme Immunoassays for Coccidioidomycosis by Using Sera from a Region of Endemicity and a Region of Nonendemicity. Clin Vaccine Immunol. 2015 Oct;22(10):1090-5. doi: 10.1128/CVI.00375-15. Epub 2015 Aug 5. PMID: 26245352; PMCID: PMC4580743.
15. Martins TB, Jaskowski TD, Mouritsen CL, Hill HR. Comparison of commercially available enzyme immunoassay with traditional serological tests for detection of antibodies to Coccidioides immitis. J Clin Microbiol. 1995 Apr;33(4):940-3. doi: 10.1128/jcm.33.4.940-943.1995. PMID: 7790465; PMCID: PMC228072.
16. Kaufman L, Sekhon AS, Moledina N, Jalbert M, Pappagianis D. Comparative evaluation of commercial Premier EIA and microimmunodiffusion and complement fixation tests for Coccidioides immitis antibodies. J Clin Microbiol. 1995 Mar;33(3):618-9. doi: 10.1128/jcm.33.3.618-619.1995. PMID: 7751365; PMCID: PMC228000.
17. Blair JE, Mendoza N, Force S, Chang YH, Grys TE. Clinical specificity of the enzyme immunoassay test for coccidioidomycosis varies according to the reason for its performance. Clin Vaccine Immunol. 2013 Jan;20(1):95-8. doi: 10.1128/CVI.00531-12. Epub 2012 Nov 15. PMID: 23155124; PMCID: PMC3535779.
18. Kuberski T, Myers R, Wheat LJ, Durkin M, Connolly P, Kubak BM, Bruckner D, Pegues D. Diagnosis of coccidioidomycosis by antigen detection using cross-reaction with a Histoplasma antigen. Clin Infect Dis. 2007 Mar 1;44(5):e50-4. doi: 10.1086/511684. Epub 2007 Jan 25. PMID: 17278049.
19. Thompson GR 3rd, Bays DJ, Johnson SM, Cohen SH, Pappagianis D, Finkelman MA. Serum (1->3)-β-D-glucan measurement in coccidioidomycosis. J Clin Microbiol. 2012 Sep;50(9):3060-2. doi: 10.1128/JCM.00631-12. Epub 2012 Jun 12. PMID: 22692738; PMCID: PMC3421794.]
20. Zangeneh TT, Malo J, Luraschi-Monjagatta C, Hage CA, Wheat LJ, Strawter C, Klotz SA, Knox KS. Positive (1-3) B-d-glucan and cross reactivity of fungal assays in coccidioidomycosis. Med Mycol. 2015 Feb 1;53(2):171-3. doi: 10.1093/mmy/myu077. Epub 2014 Dec 24. PMID: 25541557.
21. Saubolle MA, Wojack BR, Wertheimer AM, Fuayagem AZ, Young S, Koeneman BA. Multicenter Clinical Validation of a Cartridge-Based Real-Time PCR System for Detection of Coccidioides spp. in Lower Respiratory Specimens. J Clin Microbiol. 2018 Jan 24;56(2):e01277-17. doi: 10.1128/JCM.01277-17. PMID: 29212702; PMCID: PMC5786707.
22. Donovan FM, Ramadan FA, Khan SA, Bhaskara A, Lainhart WD, Narang AT, Mosier JM, Ellingson KD, Bedrick EJ, Saubolle MA, Galgiani JN. Comparison of a Novel Rapid Lateral Flow Assay to Enzyme Immunoassay Results for Early Diagnosis of Coccidioidomycosis. Clin Infect Dis. 2021 Nov 2;73(9):e2746-e2753. doi: 10.1093/cid/ciaa1205. PMID: 32818956.
23. Thompson GR 3rd, Boulware DR, Bahr NC, Clancy CJ, Harrison TS, Kauffman CA, Le T, Miceli MH, Mylonakis E, Nguyen MH, Ostrosky-Zeichner L, Patterson TF, Perfect JR, Spec A, Kontoyiannis DP, Pappas PG. Noninvasive Testing and Surrogate Markers in Invasive Fungal Diseases. Open Forum Infect Dis. 2022 Mar 4;9(6):ofac112. doi: 10.1093/ofid/ofac112. PMID: 35611348; PMCID: PMC9124589.

APPENDIX: AKA this is the old testing or at least how it works