Headaches That Persist May Have a Fungus That Exists.

Case Report: A brief history of the present illness:
A 48-year-old man with a history of ischemic stroke and coronary artery disease presented to the primary care clinic with complaints of a constant headache, malaise, and poor appetite for two months. He also reported progressive shortness of breath for 6 months and had 60 pounds of weight loss in 4 months. On review of systems, he had generalized body aches, joint pain and abdominal discomfort, but he denied any fever. Blood samples were collected in the clinic and the next day he was referred to an emergency room as he was noted to have hypercalcemia with a corrected calcium level of 12 mg/dl (8.5 - 10.5 mg/dl) and hyperglycemia 495 mg/dl (70 - 100 mg/dl). A month earlier, he had a hospital admission for hypercalcemia and was discharged once his serum calcium level returned to normal with intravenous hydration and pamidronate. The patient continued to experience fatigue after that hospital discharge.
Past medical history including allergies:
Coronary artery disease, type II diabetes mellitus, ischemic stroke, ischemic cardiomyopathy, essential hypertension, peripheral arterial disease, abdominal aortic aneurysm repair and thrombotic thrombocytopenic purpura.
Allergic rash to neomycin in the past.
Key medications:
Insulin, aspirin, atorvastatin and carvedilol.
Epidemiological history:
 He lived at home with his wife. He had a pet dog, and he worked as a construction engineer. He smoked 4-5 cigarettes per day, and he drank alcohol occasionally. There was no history of substance abuse. He traveled to Missouri 2 months prior to the presentation.
Physical examination:
The patient appeared tired and cachectic. The blood pressure at presentation was 124/67 mm Hg, heart rate was 86 beats per minute, temperature 36.6 °C (97.9 °F), and respirations were 15 breaths per minute. The examination was significant for hepato-splenomegaly. Meningeal signs were absent, and he had a flat affect.
Studies:
 Complete blood count revealed pancytopenia. CRP was elevated to 10.3 mg/L (reference < =9.00 mg/L). Fourth-generation HIV test and serum cryptococcal antigen were negative. His intact parathyroid hormone level (PTH) was < 6.3 pg/ml (18.4 - 80.0 pg/ml) and PTHrP (parathyroid hormone-related peptide) was elevated to 5.2 (reference < 2). Non-contrast CT scan of the chest demonstrated centrilobular ground-glass nodularity and a solid 9 mm nodule in the right middle lobe. Left adrenal hypertrophy and hepato-splenomegaly were noted on a non-contrast CT scan of the abdomen. MRI of the brain revealed several small foci of T2/flair hyper-intensities throughout the subcortical white matter of both cerebral hemispheres and posterior limb of the left internal capsule (Figure 1). On bone marrow biopsy, he had a mild to moderate increase in T cells without any evidence of monotypic plasma cells. Lung biopsy of the nodule revealed a large necrotizing granuloma with central necrosis. Liver biopsy was consistent with numerous scattered loosely-formed granulomas. (Figure 2)
Clinical course prior to diagnosis:
Prior to admission, he had an extensive workup for pancytopenia, weight loss and recurrent hypercalcemia requiring intravenous pamidronate therapy.  His Vitamin D 1, 25-OH levels were normal. ANA, ANCA, SS-A/B, anti-cardiolipin IgG/IgM and para-neoplastic screen were negative. Multidisciplinary team management included rheumatology, endocrinology, nephrology, hematology-oncology and neurology consultation. During this hospital course, his serum calcium level normalized after aggressive intravenous hydration, but he continued to complain of headaches and generalized fatigue.
Differential diagnosis:

• Malignant hypercalcemia


• Neuro-sarcoidosis


• Disseminated histoplasmosis with central nervous system involvement


• Central Nervous System (CNS) Tuberculosis


• Granulomatosis with polyangiitis


• Lymphoma

 
Diagnostic procedures and results:
As he resided in an endemic region and his sub-acute presentation with a chronic headache could be seen with central nervous system histoplasmosis, a qualitative urine Histoplasma antigen was tested and resulted positive. Also, serum Histoplasma antigen was noted to be elevated (55.8 ng/ml).  At that point, lumbar puncture was performed showing clear cerebrospinal fluid (CSF)  with 3 nucleated cells/uL, 26 RBCs/uL, glucose 61 mg/dl and protein 107 mg/dl. CSF Histoplasma antigen was elevated to 2.14 ng/ml, and his CSF Histoplasma mycelial antibody titer was 1:32. These results were all consistent with disseminated histoplasmosis with CNS involvement.
Treatment/follow-up:
He was treated with a 6-week course of intravenous liposomal amphotericin B followed by oral itraconazole for a planned one-year course. His headache resolved within 2 weeks of starting therapy. Urine and serum Histoplasma antigens were monitored during therapy, and urine Histoplasma antigen decreased to < 0.5 ng/mL and serum Histoplasma antigen was down to 1.73 ng/mL after 8 weeks of therapy.
A brief discussion of differential/major teaching points of case:
 Histoplasma capsulatum is a dimorphic fungus. It is endemic in the Mississippi and Ohio River valley in the United States and exists in the soil contaminated with large amounts of bird or bat guano. Infection results from inhalational exposure to the molds during day-to-day occupational and recreational activities¹. Less than 1% of people develop moderate to severe symptoms after exposure². CNS involvement accounts for 5-10% of disseminated disease³. Despite prolonged courses of treatment, the reported case fatality was 39% with half of the survivors relapsing in a prior study.³ Patients at risk include those with AIDS, transplant recipients, hematologic malignancies, and those on high-dose corticosteroids or TNF-alpha blocker therapy due to weakened cell-mediated immunity. ⁴
In the case of CNS involvement, clinical features range from persistent headache to focal cranial nerve palsies, chronic meningitis, focal brain or spinal cord lesions, stroke syndromes, encephalitis and hydrocephalus.^5,6
The diagnosis is often delayed because of failure to consider histoplasmosis in cases of chronic meningitis and unfamiliarity with the tests required for diagnosis.⁷ It requires a combination of diagnostic tests on serum and CSF samples as no single test exhibits sufficient sensitivity for CNS disease.⁸ Abnormalities in CSF analysis are mostly similar to other fungal meningitis and tuberculous meningitis. Histoplasma antigen is present in up to 66% of CSF samples with CNS involvement. The sensitivity of the CSF Histoplasma antibody ranges from 80% to 89%, however it is plausible that immune-suppression can result in lower sensitivity.⁹ CNS involvement should also be considered in the presence of compatible clinical symptoms and confirmation of disseminated disease by diagnostic studies. Workup should include a histopathological examination of the biopsy of other sites of suspected involvement, fungal blood culture, serologic testing of serum for anti- Histoplasma antibodies and antigen testing of blood and urine. However, the diagnostic work-up should be repeated at least once, including a culture of at least 10 mL of CSF, in the case of high pretest probability and non-revealing initial CSF results.¹⁰
Infectious Diseases Society of America (IDSA) recommends treating CNS histoplasmosis with liposomal amphotericin B for four to six weeks, followed by itraconazole for at least one year and until clinical resolution of disease.¹¹ This was the same regimen we followed for our patient.
This case highlights the need to maintain a high index of suspicion for CNS histoplasmosis in immunocompetent hosts from an endemic area when they present with compatible neurologic symptoms. It also demonstrates the importance of obtaining appropriate serologic studies on CSF in the diagnosis of CNS histoplasmosis.
Final diagnosis:
Disseminated histoplasmosis with central nervous system involvement and recurrent hypercalcemia in an immunocompetent patient.
 

References:

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2. Carol A. Kauffman. Histoplasmosis: Clinical and Laboratory Update. Clinical Microbiology Reviews Jan 2007, 20 (1) 115-132. PMID: 17223625


3. Wheat LJ, Batteiger BE, Sathapatayavongs B. Histoplasma capsulatum infections of the central nervous system. A Clinical Review. Medicine (Baltimore) 1990;69:244–60. PMID: 21772588


4. Kauffman, C. A., K. S. Israel, J. W. Smith, A. C. White, J. Schwarz, and G. F. Brooks. 1978. Histoplasmosis in immunosuppressed patients. Am. J. Med. 64:923-932. PMID: 350045


5.  Ellner JJ, Bennett JE. Chronic meningitis. Medicine (Baltimore) 1976;55:341–69. PMID: 957996


6. Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis 2005;40:844–52. PMID: 15736018


7. Wheat J, Myint T, Guo Y, et al. Central nervous system histoplasmosis: Multicenter retrospective study on clinical features, diagnostic approach and outcome of treatment. Medicine (Baltimore). 2018;97(13):e0245. PMID: 29595679


8. Wheat, L. J., E. J. Sith, and B. Sathapatayavongs. 1983. Histoplasmosis in renal allograft recipients: two large urban outbreaks. Arch. Intern. Med. 143:703-707 PMID: 6301394


9. Wheat, L. J. 2001. Laboratory diagnosis of histoplasmosis: update 2000. Semin. Respir. Infect. 16:131-140. PMID: 11521245


10. Goodwin, R. A., Jr., J. L. Shapiro, G. H. Thurman, S. S. Thurman, and R. M. des Prez. 1980. Disseminated histoplasmosis: clinical and pathological correlations. Medicine (Baltimore) 59:1-33. PMID: 7356773


11. Wheat L. J. et al, Clinical Practice Guidelines for the Management of Patients with Histoplasmosis: 2007 Update by the IDSA, Clin Infect Dis. 2007; 45(7): 807–25. PMID: 17806045