Episode 143: Pulmonary Cocci Basics - a podcast by Rio Bravo Family Medicine Residency Program

Episode 143: Pulmonary Cocci Basics

Dr. Lovedip Kooner explains the history, diagnosis, and treatment of pulmonary coccidioidomycosis (cocci for short.) Disseminated cocci infection was also discussed. Dr. Arreaza added some anecdotes of patients seen with this infection.  

Written by Lovedip Kooner, MD. Comments by Hector Arreaza, MD. 

You are listening to Rio Bravo qWeek Podcast, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California, a UCLA-affiliated program sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. This podcast was created for educational purposes only. Visit your primary care provider for additional medical advice.

Definition:

Coccidioidomycosis, also known as Valley Fever, is an infection caused by the fungi Coccidioides immitis and Coccidioides posadasii. Coccidioides is also referred to as cocci. Generally speaking, C. immitis is found in California and C. posadasii is found in Arizona, and Central and South America. More recently Cocci has also been found as far north as Washington and British Columbia. 

History:

The fungal infection was first reported by Wernicke and Posadas in Argentina in 1892 where they described a case where a man had cutaneous cocci of the head, arm, and trunk. To this day, the head is preserved in Argentina. 4 For many years, only disseminated cases were recognized and described as “coccidioidal granulomas.” 

The work of Dixon and Gifford in 1935 elucidated that a pneumonic disease of unknown cause termed “San Joaquin Valley Fever” was, in fact, the primary coccidioidal infection and the port of entry of almost all coccidioidal disease. Initial infection occurs predominantly by inhalation of aerosolized arthroconidia and rarely by direct cutaneous inoculation.1,2

Coccidioides spp. survive best in areas with low rainfall (12–50 cm per year), limited winter freezes, and alkaline soils. With climate change models, predicting the geographical range expansion.

These dimorphic fungi exist in a mycelial form in the soil. Coccidioides species have been found in animal burrows near the Kern River and in Armadillo burrows in South American countries like Brazil. The mycelia produce arthroconidia (spores) that are ultimately airborne and inhaled.

The inoculum required for infection is low and in animal models as few as a single arthroconidium may cause infection.3 

Infection:

Once arthroconidia are inhaled into the lung, there is typically a 1-3-week incubation period. The arthroconidia undergo morphologic changes into spherules, which are large structures that contain endospores.4 As spherules mature, they rupture and release endospores. Endospores can be spread hematogenous or through lymphatics to essentially any organ, leading to the development of new spherules and potentially disseminated disease.5 Not everyone who inhales the arthroconidia gets the infection. 

Clinical Manifestations.

About 60% of patients who inhale arthroconidia are asymptomatic. 30% have a mild respiratory illness, like the flu. 10% have a more serious disease course and are diagnosed. Other symptoms may include fever, drenching night sweats, and weight loss. Extreme fatigue that limits baseline activity may also raise concerns. Symptom onset up to 2 months after endemic exposure should lead to coccidioidomycosis on the differential. Coccidioidomycosis cases have been documented in Michigan, Europe, and China. These cases were of people who traveled to endemic areas for as little as a few days and then were later diagnosed. 

1-3% of all coccidioidomycosis cases are disseminated, severe, or chronic pulmonary infections. If undiagnosed, coccidioidomycosis may lead to significant morbidity and mortality. 

Dissemination sites include the skin, lymph nodes, bones, and Central Nervous System (CNS) which is the most severe. Any organ can be infected, including documented cases of the prostate and adrenal gland. 

Arreaza: Recap: 60% are subclinical, 30% are mild, 10% serious, 1-3% are disseminated. What are some risk factors for severe infection? Should I stop biking?

Risk factors for severe infection:

Severe pulmonary infections can happen in anyone but occur more commonly in diabetics, tobacco users, and people older than 65 years of age.

Oceanic or Filipino ethnicity and black or African American have a higher rate of dissemination. 

Immunosuppression, including HIV, transplant patients, and immunosuppressive medications like corticosteroids or TNF-alpha inhibitors have been shown to be risk factors for dissemination. 

Pregnant patients, particularly in the third trimester have higher rates of severe infection as well.

Arreaza: How do we diagnose the disease?

Diagnosis:

Diagnosis is commonly made serologically. EIA (enzyme immunoassay) is used more often. There are more false positives than false negatives and varies by manufacturer. Kern County Health Department uses Immunodiffusion IgG and IgM and Complement Fixation are used. Immunodiffusion IgG and IgM are scaled by non-reactive, weakly reactive, reactive and strongly reactive. Compliment fixations are scaled by a ratio/dilution. Serum Compliment fixations <1:2 are considered negative and 1:2 and greater are considered positive. CSF Compliment Fixation of <1:1  are considered negative and 1:1 and greater are considered positive. 

Culture or histopathology with endo-sporulating spherules can also be used to diagnose. 

Serological diagnoses are less reliable early in the disease process and may take up to 6 weeks to be positive. 

Arreaza: Let’s talk about the most common manifestation of cocci, pulmonary.

Primary pulmonary infections:

In endemic regions, 25 % of community-acquired pneumonia may be attributed to coccidioidomycosis. The primary pulmonary infection may be associated with erythema nodosum or erythema multiforme. Imaging typically demonstrates segmental or lobar consolidation and mediastinal adenopathy. 5-15% of cases are complicated by effusion. Optimal treatment is unclear, due to lack of prospective, randomized controlled clinical trials. 

Retrospective studies have shown that about 95% of immunocompetent cases resolve on their own without treatment. 

Arreaza: How do we treat it? 

Treatment:

The most recent guidelines are the 2016 Infectious Diseases Society of America Clinical Practice Guideline for the Treatment of Coccidioidomycosis (IDSA), and they recommend patient education, close observation, and supportive measures such as reconditioning physical therapy for mild or non-debilitating symptoms, or who have substantially improved or resolved their clinical illness by the time of diagnosis.

The Valley Fever Institute treats most patients with primary disease and all patients with disseminated disease; including coccidioidal meningitis, which requires lifelong treatment with a triazole.

A double-blind randomized clinical trial done by the mycosis study group showed no superiority of treatment between either fluconazole or itraconazole.

Fluconazole remains the mainstay of treatment. Fluconazole suppresses the growth of fungi, it does not directly kill fungi.

Fluconazole dosage varies from person to person, and institution to institution. Institutions from Arizona are more likely to treat with 400mg while Valley Fever Institute tends to give a minimum of 600mg-800mg/daily. 

Duration of treatment is variable; taking into consideration symptoms and serology. 

Side effects of fluconazole include xerosis, alopecia, and fatigue.

Therapeutic drug monitoring is a debated topic amongst experts. The Valley Fever Institute routinely monitors drug levels.

Arreaza: Fluconazole is the mainstay of treatment. For our primary care peers, you can start fluconazole, making sure there is no contraindication or medication interactions.

Failure of treatment.

Treatment can be stopped for intolerance and/or for treatment failure. In either case, switching to other triazoles is recommended. Those triazoles include: itraconazole, posaconazole, or voriconazole. Amphotericin B is also used for refractory cases. Each has its own dosages and adverse effect profile. 

Disseminated disease requires closer monitoring and possibly IV amphotericin, or intrathecal amphotericin. 

Arreaza: What can we expect about the future of treatment?

Future of coccidioidomycosis treatment

Although there are not any FDA-approved vaccines for fungal infections, there are vaccines being developed that have shown promise in animal models for coccidioidomycosis. 

Different drugs are also under development that have different targets than triazoles like fluconazole. 

The role of therapeutic drug monitoring may become clearer.

Further research is also needed to provide more specific guidelines.

We are optimistic about the future. We see this disease commonly in the clinic and the hospital, and many patients may become disabled in cases of complicated/disseminated cocci. This is just an introduction for our listeners to keep learning about this disease.

A message for primary care doctors: In a patient with respiratory illness, and you suspect pulmonary cocci, order serology, and chest x-ray, and if you find pulmonary cocci, start treatment with fluconazole. Learn to identify patients at risk for dissemination/severe disease and refer to infectious disease when needed. 

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Conclusion: Now we conclude episode number 143, “Pulmonary cocci basics.” Dr. Kooner explained that this fungal infection can present with symptoms of community-acquired pneumonia. He explained that infection can disseminate to other organs or cause severe disease in a small percentage of infected patients. Because of the consequences of severe infection, Dr. Arreaza recommended primary care providers keep a high level of suspicion when patients present with any symptoms compatible with cocci infection in endemic areas.

This week we thank Hector Arreaza and Lovedip [pronounced as Love-DEEP] Kooner. We give special thanks to the Valley Fever Institute for providing information for this episode. Audio editing by Adrianne Silva.

Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week! 

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References:

1. Johnson, Royce H et al. “Coccidioidomycosis: a review.” Journal of investigative medicine: the official publication of the American Federation for Clinical Research vol. 69,2 (2021): 316-323. doi:10.1136/jim-2020-001655.
2. Wernicke R: Ueber einen protozoenbefund bei mycosis fungoides. Zentralblatt Bakteriol 1892; 12:859-861.
3. Posadas A. Un nuevo caso de micosis fungiodea con posrospemias. An Cir Med Argent 1892; 15:585-97.
4. Bays, Derek J, and George R Thompson 3rd. “Coccidioidomycosis.” Infectious disease clinics of North America vol. 35,2 (2021): 453-469. doi:10.1016/j.idc.2021.03.010.
5. Nnadi NE, Carter DA. Climate change and the emergence of fungal pathogens. PLoS Pathog. 2021 Apr 29;17(4):e1009503. doi: 10.1371/journal.ppat.1009503. PMID: 33914854; PMCID: PMC8084208.
6. Gorris ME, Treseder KK, Zender CS, Randerson JT. Expansion of Coccidioidomycosis Endemic Regions in the United States in Response to Climate Change. Geohealth. 2019 Oct 10;3(10):308-327. doi: 10.1029/2019GH000209. PMID: 32159021; PMCID: PMC7007157.
7. Cordeiro, R A et al. “Phenotypic characterization and ecological features of Coccidioides spp. from Northeast Brazil.” Medical mycology vol. 44,7 (2006): 631-9. doi:10.1080/13693780600876546.
8. Davis, Matthew R et al. “Tolerability of long-term fluconazole therapy.” The Journal of antimicrobial chemotherapy vol. 74,3 (2019): 768-771. doi:10.1093/jac/dky501.
9. Galgiani, J N et al. “Comparison of oral fluconazole and itraconazole for progressive, nonmeningeal coccidioidomycosis. A randomized, double-blind trial. Mycoses Study Group.” Annals of internal medicine vol. 133,9 (2000): 676-86. doi:10.7326/0003-4819-133-9-200011070-00009.
10. Ampel, Neil M. “THE TREATMENT OF COCCIDIOIDOMYCOSIS.” Revista do Instituto de Medicina Tropical de Sao Paulo vol. 57 Suppl 19, Suppl 19 (2015): 51-6. doi:10.1590/S0036-46652015000700010.
11. Royalty-free music used for this episode: "Rain in Spain." Downloaded on October 13, 2022, from https://www.videvo.net/ 

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