Asymptomatic Coccidioidal Meningitis Relapse: A Demon in Disguise

Coccidioides spp is a soil-dwelling, dimorphic fungus that causes coccidioidomycosis. It is endemic to the western hemisphere. Although primarily a respiratory disease, it can also cause a myriad of clinical manifestations, from asymptomatic disease to meningitis. In fact, Coccidioides species is probably the most common etiologic agent of long-term meningitis in California and Arizona. Early diagnosis and treatment are critical to avoid fatal complications. With treatment, the cerebral spinal fluid analysis may return to normal. Relapse of coccidioidal meningitis is usually suspected with recurrence of meningitis symptoms. The patient is a 53-year-old man with a 2-decade history of coccidioidal meningitis who was diagnosed with an asymptomatic relapse of coccidioidal meningitis.


Introduction
Meningitis is recognized as the most serious type of dissemi nated coccidioidomycosis and if not treated is lethal. 1 This form of the disease requires prompt diagnosis and proper management by experts, which reduces the risk of serious complications such as hydrocephalus, vasculitic infarctions, cranial neuropathy, arachnoiditis, and death. 2 The Infectious Diseases Society of America's cocci dioidal guidelines indicate analyzing cerebral spinal fluid (CSF) for initial diagnosis if meningeal symptoms are pres ent and recommend initial therapy with fluconazole 400 to 1200 mg. 3 The current medical treatment is thought to only suppress the disease. 4Thus, treatment is for life, and if initial treatment fails, another oral triazole or intrathecal Amphotericin B therapy is indicated. 3Relapse is common if treatment is stopped. 5Clinical, CSF, and radiographic parameters should be used regularly to monitor treatment. 3his patient is a 53yearold man with a 2decade history of coccidioidal meningitis who was diagnosed with asymp tomatic relapsed coccidioidal meningitis.

Methods
This is a retrospective case review that is approved by Kern Medical Institutional Review Board.Literature search was performed from PubMed and Google Scholar for cocci dioidal meningitis relapse, therapeutic drug monitoring, and coccidioidomycosis.

Case Presentation
A 43yearold man had been diagnosed with coccoidal meningitis for two decades.His course was complicated by hydrocephalus and therefore underwent placement of a ventriculoperitoneal (VP) shunt.His treatment was initi ated on fluconazole 1000 mg daily.His care was compli cated by multiple VP shunt revisions: the last episode was 7 years prior.Fluconazole levels were monitored at therapeutic goal levels of 40 to 80 µg/mL.Lumbar cerebral spinal fluids (LCSF) were obtained periodically (Figure 1) to monitor his Periodically during the course of his care, he became nonadherent with medications and visits.He presented for a routine followup after a year and a half.At that visit, he admitted to being off of therapy for about 77 months as he felt "great."A lumbar puncture was performed even though he was entirely asymptomatic.His LCSF showed white blood cell (WBC) of 261 µg/mL, 80% lymphocytic, glucose of 23 mg/dL, protein of 171 mg/dL, and LCSF coccidioido mycosis CF titer of 1:8, indicating a flagrant asymptomatic relapse.Medication compliance was reinforced.Subsequent fluconazole levels were in the therapeutic range, and lumbar LCSF levels improved.

Discussion
Treatment with highdose oral fluconazole may achieve remission of coccidioidal meningitis; however, after discon tinuation of therapy, there is a high incidence of relapse. 6hus, coccidioidal meningitis requires lifelong treatment as currently understood.
Guidelines indicate that after a diagnosis and initiation of treatment for coccidioidal meningitis, LCSF analysis is recommended if the patient has meningeal symptoms, most notably headache. 3Most cases of coccidioidal meningitis relapse are symptomatic.It is uncertain the exact number of asymptomatic relapses that occur; however, the Valley Fever Institute (VFI) has experienced this before.The guidelines do not address potential asymptomatic relapse that may be a precursor to symptomatic relapse.Therefore, the VFI has routinely analyzed LCSF on a periodic basis.This and thera peutic drug monitoring allow differentiating between treat ment failure and nonadherence.In cases of treatment failure, this can lead to the escalation of therapy via dose increases or changes in medication.In cases like the one presented, it provides a tool to communicate to an asymptomatic patient that their disease is progressing.Furthermore, it prompts the physician to monitor the disease more closely.
Close followup is essential to assure maintaining response to therapy and detection of treatment failures and relapses.Therapeutic drug monitoring may lead to a suspi cion of nonadherence or therapeutic failure.Lumbar punc ture even in an asymptomatic patient can confirm or refute that concern.This case demonstrates that standardized, peri odic lumbar punctures and therapeutic drug monitoring may be useful adjuncts for preventing relapse.

Conclusion
Active coccidioidal meningitis most commonly produces meningeal symptoms.This case demonstrates that even after 2 decades of coccidioidal meningitis treatment, relapse can still occur and lifelong treatment is recommended.Relapse may be symptomatic or asymptomatic.This suggests the need for a standardized approach to monitoring disease even in asymptomatic patients that includes periodic evaluation of CSF and therapeutic drug monitoring to reduce morbidity and mortality of relapsed cocciodioidal meningitis.Therapeutic drug monitoring can also assist in differentiating between treatment failure and nonadherence.

Figure 1 .
Figure 1.Comparison of LCSF levels of WBC, glucose, and protein with noncontemporaneous serum fluconazole, from 2011 to 2022.The subset of values within the graph indicate the fluconazole levels.*VP Shunt Revision.