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Coccidioidal Meningitis

Valley fever

Coccidioidomycosis is a fungal infectious disease caused by Coccidioides spp. It is primarily a respiratory disorder, but in some case, extrapulmonary symptoms may manifest and these include, but are not limited to, coccidioidal meningitis.


In most cases, CM-Meningitis is preceded by symptomatic CM and pneumonia. Infection usually occurred weeks or months ago and patients often present with the following medical history:

  • Onset of non-specific, flu-like symptoms such as malaise, fever, chills, headaches and limb pain
  • Manifestation of a respiratory disease with additional complaints like sore throat and cough
  • Persistence of respiratory symptoms for more than a month

Rarely, CM-Meningitis develops during earlier stages of the disease, i.e., affected individuals have not passed through all of the aforedescribed phases. In any case, nausea, vomiting, decreased cognition and an altered mental status in a CM patient are highly suspicious of CM-Meningitis. Meningismus may be observed and fever may persist from the initial stage of CM, but both are not exclusion criteria for CM-Meningitis. About 50% of CM-Meningitis patients develop hydrocephalus, a condition that aggravates the symptoms described above and may additionally provoke seizures and neurological deficits. The latter may also result from cerebral infarction, a pathophysiological event seen in one out of three patients who present with CM-Meningitis [6].

  • Malaise, fever, headaches and cough are common symptoms of the latter. In a minor share of patients, this infection may persist and develop into chronic pneumonia.[symptoma.com]
  • Coccidioidal meningitis is the most severe complication of coccidioidomycosis and results from lymphohematogenous spread from the lung, manifesting as fever, headache, changes in sensorium, malaise, and meningismus.[wwwnc.cdc.gov]
  • About 2 weeks after exposure, symptomatic patients develop fever, cough, malaise, and anorexia; chest pain is often severe. Coccidioidomycosis may disseminate beyond the lungs to involve multiple organs including the meninges.[mayomedicallaboratories.com]
  • Primary infection is often complicated by prolonged cough, pleuritic chest pain, malaise, and fatigue, which can be prolonged and debilitating.[clinicaladvisor.com]
  • In children and adults, signs and symptoms include fever, malaise, weight loss, cough, and vomiting. The prodrome of tuberculous meningitis is difficult to distinguish from many common viral syndromes.[ahcmedia.com]
  • 198 Pruritus 621 199 Pruritus ani 629 200 Pruritus vulvae 631 201 Pseudofolliculitis barbae 634 202 Pseudoxanthoma elasticum 638 203 Psoriasis 640 204 Psychogenic excoriation 651 205 Pyoderma gangrenosum 654 206 Pyogenic granuloma 659 207 Radiation dermatitis[books.google.com]
  • Its use often results in dermatitis and photosensitization, a problem in areas endemic for coccidioidomycosis. Posaconazole is available only in a liquid formulation. It is a potent inhibitor of CYP3A4.[clinicaladvisor.com]
Blurred Vision
  • On day 5 of admission, blurred vision and confusion developed and rapidly progressed to obtundation. A repeat head computed tomography scan showed marked edema and transtentorial herniation, and a ventricular drain was placed.[wwwnc.cdc.gov]
  • A patient with a history of pulmonary coccidioidomycosis presented with acute confusion, blurry vision and headache. Serology confirmed basilar meningitis and magnetic resonance angiography demonstrated severe symptomatic vasospasm.[ncbi.nlm.nih.gov]
  • Of 21 patients who had an identifiable initial infection, 16 developed meningeal symptoms (most frequently headache, vomiting, and nuchal rigidity) within the next 6 months.[ncbi.nlm.nih.gov]
  • The only presenting symptom found in the majority of patients was headache. Those who were immunocompromised (most commonly HIV/AIDS and chronic steroid therapy) were at increased risk, but diabetics were not at increased risk.[ncbi.nlm.nih.gov]
  • Headaches, nausea, vomiting and encephalopathy are characteristic for CM-Meningitis.[symptoma.com]
  • The presence of a headache was significantly associated with meningitis (P Pooled estimates for the sensitivity, specificity, likelihood ratio positive and likelihood ratio negative of 1) at least one CNS disease sign or symptom and 2) headache alone[journals.plos.org]
  • A patient with a history of pulmonary coccidioidomycosis presented with acute confusion, blurry vision and headache. Serology confirmed basilar meningitis and magnetic resonance angiography demonstrated severe symptomatic vasospasm.[ncbi.nlm.nih.gov]
  • No patient discontinued therapy because of drug-related side effects, although confusion developed in two patients that resolved when the dose of fluconazole was reduced. Fluconazole therapy is often effective in suppressing coccidioidal meningitis.[ncbi.nlm.nih.gov]
  • Four months later, she presented with gait instability, confusion, and headache.[jamanetwork.com]
  • No patient discontinued therapy because of drug-related side effects, although confusion developed in two patients that resolved when the dose of fluconazole was reduced.[annals.org]
  • It is sometimes called valley fever but should not be confused with rift valley fever. Infection is caused by inhalation of airborne, fungal particles known as arthroconidia, a form of fungal spores.[icd9data.com]
Altered Mental Status
  • The major signs and symptoms exhibited by Disseminated Coccidioidomycosis are fever and chills, cough, muscle stiffness and aches, altered mental status, and swelling of the joints.[dovemed.com]
  • In any case, nausea, vomiting, decreased cognition and an altered mental status in a CM patient are highly suspicious of CM-Meningitis.[symptoma.com]
  • mental status. 32 Most patients with aspergillus meningitis present with altered mental status, seizures, or focal neurologic deficits.[ahcmedia.com]
  • Top of Page Signs and Symptoms Signs and symptoms of fungal meningitis may include the following: Fever Headache Stiff neck Nausea and vomiting Photophobia (sensitivity to light) Altered mental status (confusion) Diagnosis If meningitis is suspected,[cdc.gov]
Neck Stiffness
  • In September 2011, a 59-year-old man sought care in Atlanta, Georgia, USA, with new-onset headache, photophobia, and neck stiffness. He also reported fevers, chills, weight loss, dyspnea, and cough with scant hemoptysis.[wwwnc.cdc.gov]
  • […] associated with bacterial meningitis, such as neck stiffness, photophobia, and vomiting. 2 The elderly more frequently present with altered mental status and focal neurologic deficits, and less often have headache and neck stiffness. 2 In HIV-positive[ahcmedia.com]
  • However, 95% had at least two of the four symptoms of headache, fever, neck stiffness and altered mental status. [ 12 ] Most patients with viral meningitis present with subacute neurological symptoms developing over 1-7 days.[patient.info]


Previously diagnosed CM and clinical symptoms as described above should prompt analyses of specimens of cerebrospinal fluid. Cell counts are often moderately increased, with lymphocytes or neutrophil granulocytes dominating the picture. Eosinophils are not regularly detected but strongly imply CM-Meningitis. Under physiological conditions, up to 5 mononuclear cells per mm3 can be detected and granulocytes are absent. In case of CM-Meningitis, overall cell counts range between a few hundred and a few thousand per mm3. Furthermore, total protein levels may be elevated and glucose levels may be decreased.

Unfortunately, the aforementioned results are characteristic for meningitis but not specific for CM-Meningitis. If doubts remain, evidence has to be provided for the presence of Coccidioides spp. in cerebrospinal fluid. This has generally been done by histopathologic identification of spherules or by fungal culture. With regards to indirect techniques, serological tests may be performed [7]. All these methods may lack sensitivity, though. In contrast, modern, molecular biological approaches improve the specificity and possibly the sensitivity of CM-Meningitis diagnosis and are less time-consuming [8]. It is to be expected that they are established as standard diagnostic measures within the next years.

Patients should also undergo neuroimaging to assess the extent of meningitis and detect possible hydrocephalus and cerebral infarction [6]. In this regard, magnetic resonance imaging is more sensitive than computed tomography scans. For a detailed description of findings obtained by magnetic resonance images, the interested reader is referred elsewhere [9].

Cerebrospinal Fluid Abnormality
  • Patient symptoms resolved more quickly than did cerebrospinal fluid abnormalities. In 15 of 20 responding patients followed for 20 months or more, residual low-level cerebrospinal fluid abnormalities remained throughout therapy.[ncbi.nlm.nih.gov]
  • Such suppressive cisternal therapy does not replace the initial intensive use of both intravenously and intraspinally administered amphotericin B.[ncbi.nlm.nih.gov]
  • This method of administration resulted in successful suppressive treatment of one patient, including two years of follow-up without serious sequelae or relapse.[ncbi.nlm.nih.gov]
  • Currently, patients with coccidioidal infection before transplantation are maintained on lifelong infection suppression with triazole therapy.[ncbi.nlm.nih.gov]
  • There was no evidence of hepatic toxicity and no clinical evidence of adrenal insufficiency although transient adrenal suppression was demonstrated at 4 but not at 24 hours after ketoconazole administration.[ncbi.nlm.nih.gov]
  • Fluconazole therapy is often effective in suppressing coccidioidal meningitis.[ncbi.nlm.nih.gov]
Complement Fixing Antibody
  • The diagnosis is established by the discovery of a high ( 1:2) titer of complement-fixing antibody in the cerebrospinal fluid.[ncbi.nlm.nih.gov]
  • The presence of complement-fixing antibodies in CSF is diagnostic of coccidioidal meningitis and is important because CSF cultures are rarely positive.[merckmanuals.com]
  • Serum IgG antibodies are detectable by complement fixation (CF) at a later time. 12 Quantitative complement-fixing antibody titers using IgG can be used to monitor disease activity over time as they decrease with disease regression or resolution.[appliedradiology.com]
Brain Edema
  • Although he received antifungal therapy on the second emergency room visit (intravenous fluconazole), the poor outcome is not surprising considering the rapid progression of symptoms and the onset of severe brain edema.[journals.lww.com]


Nowadays, fluconazole and amphotericin B are the mainstays of CM-Meningitis treatment. Successful administration of earlier triazole antimycotics like itraconazole has been reported, but today, fluconazole is generally preferred over the former. There are, however, no clinical trials comparing the effectivity of both drugs in men [10]. Fluconazole and itraconazole are applied in a daily dose of at least 400 mg/kg per os [1]. Therapy has to be continued for at least a year, possibly life-long. Response to treatment may be assessed by regular measurements of antibody titers in cerebrospinal fluid. Close monitoring is also necessary upon cessation of treatment since recurrence is frequent. Relapses may occur months after withdrawal of antifungal medication. Triazole antimycotics may be combined with amphotericin B - voriconazole plus amphotericin B has been reported to be effective [11] -, or the latter may be applied as a stand-alone medical therapy. However, amphotericin B requires parenteral application, and is thus generally reserved for patients who don't respond well to triazole treatment. It may be administered intrathecally or intravenously.


Contrary to the often self-limiting uncomplicated form of CM, CM-Meningitis is associated with a very poor prognosis if left untreated. Early reported mortality rates neared 100%. Prognosis improved when effective antifungal drugs became available, but discontinuation of therapy bears a high risk of recurrence - even after years of uninterrupted treatment - and mortality is still high. In a retrospective study comprising 62 cases of CM-Meningitis, overall mortality was 26%. Presence of hydrocephalus and cerebral infarction has been identified as unfavorable prognostic factors that augmented the likelihood of death more than 10-fold. Patients who presented neither of those conditions had an overall mortality of 8% [6].


CM-Meningitis is the most severe complication of CM, an infectious disease caused by fungal pathogens pertaining to the genus Coccidioides. Two species have been identified so far, and they have been denominated C. immitis and C. posadasii. These species differ genetically and with regards to their distribution, whereas both are endemic in the southwestern United States. While C. immitis accounts for the vast majority of CM and CM-Meningitis cases in California and Arizona, C. posadasii is more frequently detected outside of California - in Arizona, Texas, but also outside the United States, in Mexico, Central and South America [2] Both C. immitis and C. posadasii are obligate pathogenic soil-borne fungi.

People exposed to contaminated soil, particularly after it has been whirled up either by nature or by people themselves, are at high risk of contracting CM. Exposure to soil is often related to people's profession. For instance, several dozen workers constructing solar power farms in California have developed symptomatic CM during a 30-month construction period [3]. In endemic regions, infection with Coccidioides spp. is also a common cause of community-acquired pneumonia and thus, hospitalization may be considered a risk factor for CM and CM-Meningitis [4]. People inhale arthroconidia and these eventually reach their terminal bronchioles.


C. immitis and C. posadasii are distributed throughout large parts of the western hemisphere, and there are endemic regions in the southwestern United States, in Mexico, in Central and South America. Most cases of CM are reported in California and Arizona and because of the greater prevalence of C. immitis in these geographic regions, this species is most frequently associated with CM-Meningitis. However, there is no reason to assume that C. posadasii may not cause CM-Meningitis. Extrapulmonary coccidioidomycosis has been reported in Brazil [5].

In general, the likelihood of a patient developing complications may be calculated the following way:

  • About two thirds of all CM patients manifest pneumonia.
  • 5 to 10% of patients who develop pneumonia suffers from this condition for a prolonged period of time, i.e., they develop chronic pneumonia.
  • Less than 1% of CM patients eventually presents extrapulmonary symptoms. Involvement of the central nervous system may be observed in about 20% of those cases.

According to these epidemiological data and provided that there are 150,000 cases of CM every year in the United States, less than 200 patients develop CM-Meningitis. For reasons not yet completely undersood, CM incidence has been rising in the last years [4].

The majority of this reduced group of patients is immunocompromised. Many cases of CM-Meningitis are diagnosed in people infected with the human immunodeficiency virus, in diabetes mellitus patients and in the elderly. Pregnant and post-partum women are also considered to be at higher risks than the average population.

Predilection for CM and extrapulmonary complication has been reported for Blacks and people of Asian descent, for males and patients aged 40 years and older.

Sex distribution
Age distribution


Coccidioides spp. habit in dry soil, where they develop arthrospores. The latter are sometimes also referred to as arthroconidia, and they are very light and become easily airborne. They are also very small and may reach the terminal bronchioles of a patient upon inhalation. Here, they develop into spherules, intermediate developmental stages that may measure up to 100 μm in diameter. Each spherule brings forth several hundreds, possibly thousands of endospores. These, in turn, mature, become spherules themselves and multiply the pathogenic load by releasing a new generation of endospores.

Spherules and endospores induce an inflammatory reaction that may or may not be associated with symptoms specific for a respiratory disorder. Granuloma may form and are generally associated with chronic pneumonia. Over the course of those inflammatory processes, pathogens may gain access to the cardiovascular system, namely to lymphatic and blood vessels. If this occurs, fungemia develops. Pathogens may settle in a plethora of organs that don't form part of the respiratory tract - skin, skeleton and central nervous system being the most common targets. CM-Meningitis is the most dreaded complication of CM.


Prevention of CM and CM-Meningitis consists in avoiding exposure to the etiologic agent. This applies particularly to patients pertaining to any of the above mentioned risk groups or those otherwise immunocompromised.


Coccidioidomycosis (CM) is a fungal infectious disease caused by Coccidioides spp. The are two known species belonging to this genus, namely Coccidioides immitis (C. immitis) and Coccidioides posadasii (C. posadasii). Both are obligate pathogens and cause clinically indistinguishable CM.

CM is contracted by inhalation of fungal spores that settle in the lower respiratory airways and induce an inflammatory reaction. Consequently, CM is primarily a respiratory disorder that may be limited to unspecific symptoms like malaise, fever, headaches and cough, or that may complicate and turn into a chronic pneumonia. The latter is associated with persistent chest pain, cough, hemoptysis and reduced general condition. In a minor share of patients, the disease spreads and affects extrapulmonary tissues, e.g., soft tissues, the skin, the musculoskeletal system or the central nervous system. Extrapulmonary manifestations are mainly observed in immunocompromised patients. If an inflammation of the meninges occurs, the patient is diagnosed with coccidioidal meningitis (CM-Meningitis). Headaches, nausea, vomiting and encephalopathy are characteristic for CM-Meningitis.

CM-Meningitis is a rare complication of CM, a fact that raises the question how the causative agents of that disease reach the central nervous system: Spores produced by C. immitis and C. posadasii may settle in terminal bronchioles and propagate. The systemic spread of the pathogens is generally related to a persistent infection of the lungs. The longer the inflammation persists, the higher the probability that fungi reach blood or lymphatic vessels. In most patients, however, the immune system, mainly represented by alveolar macrophages, contains the infection and reduces the pathogenic load. This is not the case in individuals infected with the human immunodeficiency virus or those that suffer from an otherwise weakened immune system. Unfortunately, these conditions do not only facilitate the development of CM-Meningitis, they also impede that the infection of the central nervous system is terminated spontaneously. Therefore, CM-Meningitis has been associated with a very high mortality before effective drugs became available.

Therapy consists in oral, intravenous or intrathecal application of antimycotic drugs, with triazole antimycotics like fluconazole and amphotericin B being the most effective compounds. Long-term, possibly life-long therapy is often required since cessation of antifungal treatment frequently causes relapses [1].

Patient Information

Coccidioidomycosis is an infectious disease caused by soil-borne fungi pertaining to the genus Coccidioides. These pathogens are distributed in the southwestern United States, Mexico, and some countries of Central and South America. The vast majority of cases is reported in California and Arizona.

Infection occurs after inhalation of spores and people who carry out soil-disruptive work, or who are exposed to contaminated soil after nature has whirled it up, are at risk of contracting coccidioidomycosis. Many people who become infected with Coccidioides remain asymptomatic, others develop a flu-like respiratory disease. Malaise, fever, headaches and cough are common symptoms of the latter. In a minor share of patients, this infection may persist and develop into chronic pneumonia. Also, pathogens may gain access to the circulation and spread to extrapulmonary tissues. Although this occurs rarely, it may have detrimental consequences, the most dreaded one being coccidioidal meningitis. Here, fungal pathogens infect the central nervous system.

This complication is mainly seen in immunocompromised patients, i.e., in people who are infected with the human immunodeficiency virus, who suffer from diabetes mellitus, in pregnant women and the elderly. Coccidioidal meningitis is associated with a high mortality and requires prolonged antifungal therapy. Failure to comply with the therapeutic regimen may cause an exacerbation of the disease or, in case of previous recovery, a life-threatening relapse.



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  2. Goldstein EJC, Johnson RH, Einstein HE. Coccidioidal Meningitis. Clin Infect Dis. 2006; 42(1):103-107.
  3. Wilken JA, Sondermeyer G, Shusterman D, et al. Coccidioidomycosis among Workers Constructing Solar Power Farms, California, USA, 2011-2014. Emerg Infect Dis. 2015; 21(11):1997-2005.
  4. Yau AA. Risk Factors and Epidemiology of Coccidioidomycosis Demonstrated by a Case of Spontaneous Pulmonary Rupture of Cavitary Coccidioidomycosis. Case Rep Infect Dis. 2016; 2016:8165414.
  5. Togashi RH, Aguiar FM, Ferreira DB, Moura CM, Sales MT, Rios NX. Pulmonary and extrapulmonary coccidioidomycosis: three cases in an endemic area in the state of Ceara, Brazil. J Bras Pneumol. 2009; 35(3):275-279.
  6. Arsura EL, Johnson R, Penrose J, et al. Neuroimaging as a guide to predict outcomes for patients with coccidioidal meningitis. Clin Infect Dis. 2005; 40(4):624-627.
  7. Kassis C, Zaidi S, Kuberski T, et al. Role of Coccidioides Antigen Testing in the Cerebrospinal Fluid for the Diagnosis of Coccidioidal Meningitis. Clin Infect Dis. 2015; 61(10):1521-1526.
  8. Vucicevic D, Blair JE, Binnicker MJ, et al. The utility of Coccidioides polymerase chain reaction testing in the clinical setting. Mycopathologia. 2010; 170(5):345-351.
  9. Erly WK, Bellon RJ, Seeger JF, Carmody RF. MR imaging of acute coccidioidal meningitis. AJNR Am J Neuroradiol. 1999; 20(3):509-514.
  10. Williams PL. Coccidioidal meningitis. Ann N Y Acad Sci. 2007; 1111:377-384.
  11. Antony SJ, Jurczyk P, Brumble L. Successful use of combination antifungal therapy in the treatment of coccidioides meningitis. J Natl Med Assoc. 2006; 98(6):940-942.

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Last updated: 2018-06-21 23:43