Histoplasma capsulatum - Adrenal Involvement: In Context of Adrenal TB and Adrenal Mass

Overview

Why the Adrenal Gland?

Histoplasma capsulatum: Adrenal Pathology in Detail

Mechanism of Adrenal Injury

1. Granuloma formation (epithelioid histiocytes ± giant cells)
2. Caseous or coagulative necrosis
3. Progressive destruction of functional cortical tissue

Figure: (A) Intracellular H. capsulatum yeast forms (2-4 μm) in BAL; (B) Adrenal biopsy H&E - necrotic area outlined by white arrows with scattered remaining adrenal cortex. GMS stain reveals this necrotic zone is packed with small Histoplasma yeasts (Tietz Textbook of Laboratory Medicine, 7th Ed., Fig. 87.26)

Clinical Presentation

• Chronic progressive disseminated histoplasmosis (PDH) is the form that typically involves the adrenal - it can appear months or years after leaving an endemic area
• Symptoms: anorexia, weight loss (91% in the 2025 Bangkok series), fatigue, fever
• Adrenal crisis (acute adrenal insufficiency) occurred in 26% in one series
• Extra-adrenal involvement: oral/pharyngeal ulcers, hepatosplenomegaly, lymphadenopathy
• Adrenal masses may reach up to 9.8 cm in size
• Mostly affects older (mean age ~64), non-HIV males

Histoplasmosis vs. Adrenal TB: Key Comparisons

Adrenal TB: Key Distinguishing Points

• Early disease (<2 years): bilateral adrenal enlargement, minimal or no calcification
• Late/chronic disease: calcification (can be dense, bilateral) + cortical atrophy

Figure: Unenhanced CT - bilateral adrenal enlargement with focal right adrenal calcification (arrow) in acute TB (Grainger & Allison's Diagnostic Radiology, Fig. 37.43)

Adrenal Incidentaloma Differential: Where Infection Fits

• Adenoma (most common single lesion, benign)
• Metastases (breast, lung - account for up to 40% of adrenal incidentalomas)
• Adrenal carcinoma (rare, ~4%)
• Granulomatous infection: TB, histoplasmosis, coccidioidomycosis, blastomycosis, paracoccidioidomycosis
• Lymphoma, sarcoidosis, amyloid, hemorrhage

Diagnosis of Adrenal Histoplasmosis

Treatment

Adrenal Histoplasmosis (Progressive Disseminated)

1. Liposomal Amphotericin B 3-5 mg/kg/day for 1-2 weeks (preferred initial therapy for moderate-severe disease)
2. Followed by Itraconazole 200 mg bid (target blood levels 2-5 μg/mL) for at least 12 months
3. Monitor urine and serum Histoplasma antigen to gauge treatment response
4. In AIDS/immunosuppressed: may need lifelong antifungal maintenance

Adrenal Insufficiency (Both TB and Histoplasmosis)

• Glucocorticoid replacement is mandatory - hydrocortisone 15-20 mg/day (AM) + 5-10 mg (PM), with fludrocortisone if mineralocorticoid deficiency
• Adrenal insufficiency is likely permanent - the 2025 Bangkok study showed all patients with AI remained on glucocorticoid supplements through 22-month follow-up despite specific treatment
• Specific antifungal/anti-TB therapy treats the infection but does not reliably restore cortical function

Adrenal TB

• Standard anti-TB regimen (HRZE for 2 months, then HR for 4-7 months)
• Same permanent AI caveat applies

Key Takeaways

1. H. capsulatum and M. tuberculosis are the two dominant infectious causes of bilateral adrenal mass with adrenal insufficiency globally.
2. Radiologically, both produce bilateral adrenal enlargement; calcification is more characteristic of TB (especially chronic/healed disease).
3. Extra-adrenal infection is absent in >50% of adrenal histoplasmosis cases - do not rely on systemic clues alone.
4. Tissue diagnosis (CT-guided biopsy + GMS stain + fungal culture / ZN stain + AFB culture) is required because the treatments are completely different.
5. Urine Histoplasma antigen is a rapid, non-invasive first-line test and should be sent in any suspected disseminated histoplasmosis case.
6. Adrenal insufficiency in both conditions is usually irreversible and requires lifelong hormonal replacement.

• Robbins & Kumar Basic Pathology, Addison Disease section, p. 760
• Robbins, Cotran & Kumar Pathologic Basis of Disease, 10th Ed., Pathogenesis section
• Harrison's Principles of Internal Medicine, 22nd Ed. (2025), Table 239-1 (Histoplasmosis diagnosis/treatment)
• Tietz Textbook of Laboratory Medicine, 7th Ed., Fig. 87.26 (adrenal biopsy histology)
• Grainger & Allison's Diagnostic Radiology, Fig. 37.43 (adrenal TB CT)
• Frameworks for Internal Medicine, Infectious causes of primary adrenal insufficiency, p. 4632
• Vorasayun T et al., "Adrenal Histoplasmosis and Tuberculosis: Clinical Presentations and a High Prevalence of Adrenal Insufficiency," Clin Endocrinol 2025 (PMID: 40205654)
• Jagadish I et al., "Case Report of Disseminated Adrenal Histoplasmosis and Secondary Adrenal Insufficiency," Cureus 2022 (PMID: 36426344)

Risks of Performing Surgery in Ischemic Stroke

Core Problem: Why Surgery is Hazardous After Ischemic Stroke

The penumbra is the main target for perioperative harm - it can be pushed into infarction by hemodynamic derangements during surgery

1. Loss of Cerebral Autoregulation

• Hypotension (common during general anesthesia, blood loss, or vasodilators) directly reduces CBF, potentially extending the infarct into the penumbra
• Hypertension (pain response, pressor use) can worsen edema, rupture fragile vessels, and cause hemorrhagic transformation

In cerebral ischemia (red curve), there is NO autoregulatory plateau - CBF is directly proportional to perfusion pressure at all levels. Any intraoperative hypotension directly reduces perfusion to the ischemic penumbra. (Morgan & Mikhail's Clinical Anesthesiology, 7th Ed., Fig. 28-1)

• Regional blood flow and metabolic abnormalities resolve after ~2 weeks
• CO2 responsiveness and blood-brain barrier may take more than 4 weeks to normalize

2. Risk of Recurrent Stroke

• The highest risk of another event is within the first month after a stroke (Miller's Anesthesia, 10th Ed.)
• Risk remains significantly elevated for at least 6 weeks for ischemic stroke and 12 weeks for hemorrhagic stroke after procedures such as total hip arthroplasty
• A 4.7-fold increased risk of ischemic stroke was reported in the first 2 weeks after major joint arthroplasty in stroke patients compared with controls

• The 2021 AHA/ASA scientific statement recommended delaying elective noncardiac surgery for at least 6 months after an acute stroke
• More recent data (cited in Miller's Anesthesia 2024) suggest the incremental risk stabilizes after 90 days, making this a more practical threshold for many patients
• Emergency surgery: If unavoidable within 2 weeks, risk of cardiovascular complications is very high. Paradoxically, if surgery must occur, doing so within 72 hours of stroke may carry lower risk than operating between days 3-14, because cerebral autoregulation deteriorates progressively over the first 5 days before recovering over 3 months

3. Hemorrhagic Transformation of the Infarct

• Reperfusion injury - restoration of blood flow to ischemic tissue causes oxidative damage and BBB breakdown
• Anticoagulant/thrombolytic continuation or initiation perioperatively
• Hypertension breaching the already-damaged blood-brain barrier

4. Medication-Related Risks

• Both VKAs and DOACs should be temporarily discontinued before surgery
• Aspirin may be selectively continued in patients with recent stroke (within 9 months) or high-risk atherosclerotic CVD
• Starting new beta-blockade in a patient awaiting noncardiac surgery significantly increases stroke risk even though it reduces cardiac risk - a critical perioperative tradeoff
• Bridging decisions must weigh thromboembolism risk against bleeding risk on a case-by-case basis

5. Anesthesia-Specific Risks

General Anesthesia

• Hypotension during induction and maintenance is almost universal - especially dangerous given absent autoregulation
• Volatile anesthetics reduce cerebral metabolic rate but also cause vasodilation and may worsen hypotension
• Delayed emergence may mask new neurological deficits

Cardiovascular Surgery (Highest Risk)

• Cardiac valve surgery (embolic risk from bypass circuit)
• Coronary artery surgery with ascending aortic atherosclerosis (atheromatous debris embolism)
• Thoracic aortic surgery (ischemia from circulatory arrest or clamp near carotid origins)
• 6% of patients experienced adverse neurological outcomes after cardiac surgery in one study

Noncardiac Surgery

• Stroke incidence: 0.08-0.4% after general surgery
• Even in known cerebrovascular disease: 0.4-3.3%
• Pathophysiology: sustained hypotension causing watershed infarctions, thrombosis, or hypertension causing hemorrhagic conversion; perioperative atrial fibrillation causing cardioembolism

6. Systemic Comorbidity Burden

• Hypertension (already-shifted autoregulatory curve, see Fig. above)
• Diabetes mellitus (poor glycemic control worsens neurological outcomes)
• Coronary artery disease (risk of perioperative MACE - Major Adverse Cardiac Events)
• Renal impairment
• Atrial fibrillation (both a cause of stroke and a perioperative arrhythmia that creates new embolic risk)
• Advanced age (independently increases stroke risk after noncardiac surgery; incidence doubles in patients >75 years)

7. Postoperative Risks Specific to Stroke Patients

Summary: Practical Risk Framework

1. Maintain blood pressure at or above the patient's baseline (avoid hypotension - "tight control")
2. Invasive arterial pressure monitoring
3. Optimize oxygenation and ventilation (avoid hypocapnia)
4. Neurological monitoring (EEG, evoked potentials, near-infrared cerebral oximetry, transcranial Doppler) for high-risk procedures
5. Careful anticoagulation management in cooperation with the treating neurologist

• Miller's Anesthesia, 10th Ed. - Cerebrovascular Disease section, p. 3993-3994
• Morgan & Mikhail's Clinical Anesthesiology, 7th Ed. - Cerebrovascular Disease (Figs. 28-1 and 28-2), pp. 1147-1149
• Miller's Anesthesia, 10th Ed. - Stroke (Orthopedic/Geriatric surgery), p. 9154
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Ed. - Perioperative ischemic evaluation
• AHA/American Stroke Association 2021 Scientific Statement (cited in Miller's, ref. 258)

Urological Surgery and Ischemic Stroke: Risks and Considerations

Important Clarification First

General Surgical Risks After Ischemic Stroke (Applies to All Surgery)

• CVA, ACS, and AMI in the year after elective surgery were 2.12 times more frequent after prior cardiovascular events
• The risk of postoperative stroke plateaued only after a 20-month interval from the stroke to surgery
• Risk of cardiac events (ACS/AMI) remained elevated for up to 37 months after a major cardiovascular event

Why Urological Surgery Specifically Compounds These Risks

1. Patient Demographics - The Overlap Problem

• Older men (average age 65+ for bladder cancer, older for BPH)
• With comorbid hypertension, atherosclerosis, coronary artery disease
• On long-term antiplatelet or anticoagulant therapy for the same cardiovascular disease that caused their stroke

2. Anticoagulation Dilemma - Especially Acute in Urology

• Antiplatelet agents (aspirin, clopidogrel)
• Anticoagulants (warfarin, DOACs) - particularly if stroke was cardioembolic (AF)

• TURP / TURBT: highly vascular transurethral resection - requires stopping antiplatelets and anticoagulants
• Radical cystectomy: major pelvic surgery with significant blood loss (transfusion frequently needed)
• Nephrectomy: major abdominal/retroperitoneal dissection

3. TURP / TURBT-Specific Risk: Irrigation Fluid Absorption (TURP Syndrome)

• Acute hyponatremia (dilutional) and hypoosmolality
• Cerebral edema - in a brain already injured by ischemia and with a compromised blood-brain barrier, even mild cerebral edema can be catastrophic
• Fluid overload, pulmonary edema, cardiovascular decompensation

4. Laparoscopic / Robotic Urological Surgery: Pneumoperitoneum + Trendelenburg

• Raised ICP from pneumoperitoneum can worsen cerebral ischemia and edema in the infarcted zone
• Hypercarbia from CO2 absorption causes cerebral vasodilation and further ICP rise
• The steep Trendelenburg position (>30°, as used in robotic prostatectomy) is maintained for prolonged periods, with documented cases of upper airway edema, ischemic optic neuropathy, and raised ICP

5. Hypotension During Major Urological Surgery

6. Spinal/Neuraxial Anesthesia Considerations

• Sympathetic blockade - acute hypotension (vasodilation below block level)
• Loss of normal baroreceptor compensation in the lower body

Summary: Why the Risk Is Considered "Too High" for Elective Urological Surgery

What the Guidelines Say

• AHA/ASA (2021): Delay elective noncardiac surgery for at least 6 months after acute ischemic stroke
• Emerging evidence (Miller's Anesthesia 10th Ed.): Risk stabilizes after 90 days - this may be the more practical threshold
• Luney et al., 2025: Stroke risk plateaus only after ~20 months in real-world data
• Emergency urological surgery (e.g., obstructing urosepsis, ruptured kidney) cannot wait and should proceed with maximal neurological precautions regardless of stroke timing

Bottom Line

• Morgan & Mikhail's Clinical Anesthesiology, 7th Ed. - Urological surgery and Cerebrovascular Disease sections
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Ed. - Physiology of Pneumoperitoneum, Table 50-5
• Miller's Anesthesia, 10th Ed. - Cerebrovascular Disease perioperative management
• Luney MS et al., "Adverse outcomes after surgery after a cerebrovascular accident," Br J Anaesth 2025 (PMID 39384506)