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].

• Fever

  Symptoms There are three different types of valley fever. Acute valley fever Valley Fever is most common in Arizona. Initial symptoms are mild. [medicalnewstoday.com]

  Valley Fever Diagnosis Often Missed. 2016. Press release. [infectiousdiseaseadvisor.com]

  The ICD code B38 is used to code Coccidioidomycosis Coccidioidomycosis (/kɒkˌsɪdiɔɪdoʊmaɪˈkoʊsɪs/, kok-sid-ee-oy-doh-my-KOH-sis), commonly known as cocci, "valley fever", as well as "California fever", "desert rheumatism", and "San Joaquin Valley fever [icd.codes]

  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]

  Also called: Coccidioidomycosis Valley Fever is a disease caused by a fungus (or mold) called Coccidioides. [icdlist.com]

• Pain

  They may include: skin lesions skull lesions, which are often painful lesions in the spine and other bones swollen joints, which are usually painful meningitis, or inflammation of the membranes around the brain and the spinal cord muscle aches and stiffness [medicalnewstoday.com]

  Of those that do experience symptoms, the most common symptoms tend to be mild and flu-like, including: Fever Headache Cough Fatigue Chest pain Chills Shortness of breath (dyspnea) Muscle pain (myalgia) Joint pain (arthralgia) A rash will develop in around [verywell.com]

  When the infection is in your lungs, it can cause flu-like symptoms, such as: a cough chest pain a fever chills night sweats fatigue joint aches a red, spotty rash shortness of breath This type of infection is commonly known as valley fever. [healthline.com]

  He denied positional component, neck pain, or infectious symptoms. He had no improvement with scopolamine patches, fioricet, rizatriptan, sumatriptan, rimegepant, or ibuprofen. [n.neurology.org]

  […] asymptomatic or present as a mild to serious flu-like illness marked chiefly by fever, cough, sore throat, headache, fatigue, and pneumonia but sometimes becoming disseminated beyond the lungs especially to the skin, bones, joints, and meninges resulting in painful [merriam-webster.com]

• Asymptomatic

  \ : a disease especially of humans and domestic animals that is caused by inhalation of spores from either of two fungi ( Coccidioides immitis or C. posadasii ) found in dry soils of the southwestern U.S., Mexico, and Central America and that may be asymptomatic [merriam-webster.com]

  Pulmonary infection is the most common clinical manifestation, however the spectrum of disease ranges from asymptomatic exposure with subsequent immunity, to severe and life-threatening disseminated disease [1], [3]. [journals.plos.org]

  Coccidioidomycosis is a pulmonary or hematogenously spread disseminated disease caused by the fungi Coccidioides immitis and C. posadasii ; it usually occurs as an acute benign asymptomatic or self-limited respiratory infection. [merckmanuals.com]

  Patients with nodules are usually asymptomatic. Upper lobe cavitation may resemble chronic pulmonary aspergillosis or tuberculosis. Patients develop chronic productive cough, haemoptysis, weight loss and chest pains. [life-worldwide.org]

• Weakness

  Factors) The risk factors for Disseminated Coccidioidomycosis include: Individuals living in the endemic regions; travelling to areas that include the South Western New Mexico, Arizona, California, San Joaquin Valley, and Western Texas Individuals with weak [dovemed.com]

  Anyone can get meningitis, but it is more common in people with weak immune systems. Meningitis can get serious very quickly. [icdlist.com]

  The most common cause of fungal meningitis for people with weak immune systems is Cryptococcus. This disease is one of the most common causes of adult meningitis in Africa. How it Spreads Fungal meningitis is not spread from person to person. [cdc.gov]

  Weak immune system : People with a weakened immune system have a higher risk of infection and complications. This includes patients with HIV or AIDS, and those receiving steroid medications, chemotherapy, or immunosuppressant drugs. [medicalnewstoday.com]

• Malaise

  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]

  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]

  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]

  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]

• Vomiting

  Two patients were failures from nausea and vomiting, and the remaining seven either improved or experienced remission. [ncbi.nlm.nih.gov]

  Abstract A 35-year-old man with known coccidioidal meningitis developed a severe headache and vomiting during routine treatment. [synapse.koreamed.org]

• Jaundice

  NB : ceftriaxone should not be used in premature babies or in babies with jaundice, hypoalbuminaemia or acidosis, as it may exacerbate hyperbilirubinaemia. [patient.info]

• Ulcer

  The symptoms depend on where the infection spreads but can often include: ulcers, skin lesions, or nodules that are more serious than a rash lesions in bones, including the skull or spine painful and swollen joints, especially in the knees or ankles meningitis [healthline.com]

  Complications can include: Skin ulcers and abscesses Swollen and painful joints Bone lesions Heart inflammation Urinary tract problem Meningitis Meningitis is by far the most serious complication. [verywell.com]

  The patient can develop skin ulcers, bone lesions, abscesses, severe joint pain, inflammation of the heart, problems with the urinary tract, and meningitis. [medicalnewstoday.com]

  […] aches Altered mental status Increased sensitivity to light Arthritis: Swelling of the joints, joint pain; swelling is generally found in the ankle, feet and legs Erythema nodosum - rashes and painful lumps on the lower legs Occurrence of skin nodules, ulcers [dovemed.com]

  Primary cutaneous coccidioidomycosis manifests as an ulcerated nodule at the site of inoculation, sometimes accompanied by regional lymphadenopathy. [clinicaladvisor.com]

• Arthralgia

  Of those that do experience symptoms, the most common symptoms tend to be mild and flu-like, including: Fever Headache Cough Fatigue Chest pain Chills Shortness of breath (dyspnea) Muscle pain (myalgia) Joint pain (arthralgia) A rash will develop in around [verywell.com]

  A rash often develops within 1 to 2 days, followed by erythema nodosum or multiforme and accompanying arthralgias. About 2 weeks after exposure, symptomatic patients develop fever, cough, malaise, and anorexia; chest pain is often severe. [mayomedicallaboratories.com]

  Other symptoms include night sweats, chest pain, chills, arthralgias, headaches, myalgias, wheezing, skin rashes, stiff neck, sore throat, weight loss, and hemoptysis. [clinicaladvisor.com]

  The other 40% develop a mild to moderate influenza-like syndrome 1 to 3 weeks (17) after exposure that includes cough, fever, night sweats, pleuritic chest pains, arthralgias, myalgias, fatigue, and anorexia. [microbewiki.kenyon.edu]

  […] maculopapular rash, erythema nodosum, or erythema multiforme may help point to the specific diagnosis of coccidioidomycosis. 1, 6 The syndrome of “valley fever” or “desert rheumatism” develops in about 25% of those infected and comprises the triad of arthralgia [appliedradiology.com]

• Hearing Impairment

  In developed countries, the rate of mortality from bacterial meningitis among neonates has decreased but there has not been a significant decrease in long-term complications such as cerebral palsy, learning disability, seizures and hearing impairment. [patient.info]

• Photophobia

  A lumbar puncture with analysis of cerebrospinal fluid (CSF) should be done in any patient with suspected or previously diagnosed coccidioidomycosis presenting with a headache, blurry vision, photophobia, meningismus, decline in cognition, hearing changes [health.ucdavis.edu]

  Top of Page Signs and Symptoms Signs and symptoms of fungal meningitis include the following: Fever Headache Stiff neck Nausea and vomiting Photophobia (eyes being more sensitive to light) Altered mental status (confusion) Diagnosis If a doctor suspects [cdc.gov]

  […] lesions in the spine and other bones swollen joints, which are usually painful meningitis, or inflammation of the membranes around the brain and the spinal cord muscle aches and stiffness headaches fever neck or shoulder stiffness change in mental status photophobia [medicalnewstoday.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]

• Headache

  Background: Thunderclap headache refers to a headache that reaches its maximal intensity within seconds and is considered a “red flag” for secondary headaches. [n.neurology.org]

  Abstract A 35-year-old man with known coccidioidal meningitis developed a severe headache and vomiting during routine treatment. [synapse.koreamed.org]

  The most common symptom is headache, present in 75% of patients 2. [radiopaedia.org]

  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]

• 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]

  Other symptoms can include altered mental status, fever, personality changes, and focal neurological deficits. Our literature review found no cases of coccidioidal meningitis presenting with thunderclap headache. [n.neurology.org]

  mental status. 32 Most patients with aspergillus meningitis present with altered mental status, seizures, or focal neurologic deficits. [ahcmedia.com]

  Past surgical history included an insertion of Omaya reservoir nine months before admission for intrathecal chemotherapy, which was removed due to postoperative complications including altered mental status, intracranial, and ventricular hemorrhage. [ncbi.nlm.nih.gov]

  Top of Page Signs and Symptoms Signs and symptoms of fungal meningitis include the following: Fever Headache Stiff neck Nausea and vomiting Photophobia (eyes being more sensitive to light) Altered mental status (confusion) Diagnosis If a doctor suspects [cdc.gov]

• Confusion

  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]

  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]

• Focal Neurological Deficit

  Other symptoms can include altered mental status, fever, personality changes, and focal neurological deficits. Our literature review found no cases of coccidioidal meningitis presenting with thunderclap headache. [n.neurology.org]

  Paresis, focal neurological deficits (including cranial nerve involvement and abnormal pupils). Seizures. [patient.info]

• Personality Change

  Other symptoms can include altered mental status, fever, personality changes, and focal neurological deficits. Our literature review found no cases of coccidioidal meningitis presenting with thunderclap headache. [n.neurology.org]

  Altered mental status, with or without fever, personality changes, nausea, vomiting, and focal neurological deficits may be additional findings. Physical examination will reveal some degree of meningismus in ∼50% of the cases. [academic.oup.com]

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]

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.

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].

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.

1. Ampel NM. The Treatment of Coccidioidomycosis. Rev Inst Med Trop Sao Paulo. 2015; 57 Suppl 19:51-56.
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.
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