01Approach to the Critical Patient/attcp43

Immediate stabilization

›Airway and oxygenation threats

›Laryngeal or oropharyngeal lesion compromising airway patency

›Hoarseness, stridor, or drooling as warning signs

›If impending obstruction, early definitive airway control

›Respiratory failure from extensive pulmonary infiltrates

›SpO2 target 92–96%

›HFNC for hypoxemia refractory to low-flow oxygen

›If SpO2 < 90% on room air, escalate oxygen delivery immediately

›Avoid NIV if secretion burden is high

›Early intubation planning for ventilatory failure

›Hemodynamic and adrenal threats

›Adrenal crisis from bilateral adrenal gland destruction

›Hypotension refractory to fluids

›Hyponatremia, hyperkalemia, hypoglycemia

›If adrenal crisis suspected, IV hydrocortisone 100 mg immediately

›Follow with hydrocortisone 50 mg every 6 hours

›Concurrent normal saline resuscitation

›Septic shock from disseminated disease

›MAP target >= 65 mmHg

›Norepinephrine if fluid-unresponsive hypotension

Escalation and consult triggers

›Immediate consultation indications

›Infectious disease for all confirmed or probable cases

›Antifungal selection and monitoring guidance

›Treatment duration determination

›Critical care for respiratory failure or hemodynamic instability

›ICU-level monitoring

02History/hx41

Exposure and travel history

›Endemic area residence or travel

›Current or prior residence in Latin America, especially Brazil

›Brazil accounts for approximately 80% of global cases

›Reactivation can occur up to 50 years after leaving endemic area

›Rural or agricultural occupation

›Soil exposure during farming, construction, or excavation

›69% of cases in one series were agricultural workers

›Return traveler presentation

›Immigration history from Colombia, Venezuela, Argentina, Paraguay

Symptom characterization

›Pulmonary symptoms

›Chronic cough duration

›Weeks to months in adult chronic form

›More rapid onset in juvenile form

›Dyspnea on exertion

›Sputum production; hemoptysis suggests TB overlap

›Oropharyngeal and mucosal symptoms

›Oral pain, odynophagia, dysphagia

›Oral mucosal lesions present in approximately 90% of chronic cases

›Hoarseness suggesting laryngeal involvement

›Nasal obstruction or discharge

›Constitutional symptoms

›Fever, night sweats, unintentional weight loss

›Fatigue and malaise

›Alarm symptoms requiring urgent evaluation

›Neurological: headache, seizures, focal deficits (CNS involvement)

›Dizziness, syncope, salt craving (adrenal insufficiency)

03Physical Exam/exam39

Vitals and general assessment

›Stability snapshot

›Temperature: fever in active disease; hypothermia in severe dissemination

›Blood pressure: hypotension suggesting adrenal crisis or septic shock

›SBP < 90 mmHg or MAP < 65 mmHg as critical thresholds

›Respiratory rate: tachypnea indicating pulmonary compromise

›Oxygen saturation on room air

›General appearance

›Cachexia and malnutrition (common in affected populations)

›Hyperpigmentation of skin (Addisonian features from adrenal involvement)

Oropharyngeal and mucosal exam

›Oral cavity findings

›Mulberry-like (moriform) ulcers of gingiva, palate, lips, and pharynx

›Pathognomonic "mulberry stomatitis" with hemorrhagic punctate dots

›Present in approximately 90% of chronic PCM cases

›Granulomatous plaques on buccal mucosa

›Microstomy (reduced oral aperture) from fibrosis

›Laryngeal and nasal exam

›Hoarseness on voice assessment

›Nasal septal involvement (less common than in mucocutaneous leishmaniasis)

›Stridor indicating laryngeal compromise

Lymph node and skin exam

›Lymphadenopathy pattern

›Generalized or regional lymphadenopathy

›Suppurative or fistulizing nodes in 27% of pediatric cases

›Cervical and submandibular most common sites

›Mediastinal lymphadenopathy (juvenile form)

›Skin lesions

04Differential Diagnosis/ddx32

Life-threatening mimics

›Pulmonary tuberculosis

›Most important mimic; co-infection is common (ICD-10 A15.0)

›Differentiating feature: AFB smear/culture positive in TB

›PCM and TB co-infection requires treatment of both

›Overlapping chest imaging and lymphadenopathy

›Hematologic malignancy

›Hodgkin and non-Hodgkin lymphoma (ICD-10 C81–C85)

›Diffuse lymphadenopathy in juvenile form mimics lymphoma

›Biopsy with staining differentiates

›Leukemia in pediatric cases with hepatosplenomegaly and cytopenias

Infectious mimics

›Histoplasmosis (ICD-10 B39)

›Similar endemic mycosis with overlapping geography

›Histoplasma capsulatum produces smaller intracellular yeast

›Urinary antigen test positive in histoplasmosis

›Co-endemic in Brazil and Colombia

›Mucocutaneous leishmaniasis (ICD-10 B55.1)

›Overlapping endemic areas; nasal lesions favor leishmaniasis

›Oral mucosal lesions with hemorrhagic dots favor PCM

›PCL rK39 serology or biopsy differentiates

›Leishmania destroys nasal septum; PCM rarely perforates septum

›Other endemic mycoses

›Coccidioidomycosis (ICD-10 B38): southwestern US and Latin America

›Blastomycosis (ICD-10 B40): North American distribution

›Sporotrichosis (ICD-10 B42): lymphocutaneous pattern

Non-infectious mimics

›Squamous cell carcinoma (ICD-10 C06)

05Laboratory Tests/lt64

Microbiologic confirmation

›Direct microscopy (KOH preparation or calcofluor white)

›Specimen types: sputum, skin scraping, lymph node aspirate, bronchoalveolar lavage

›Lymph node aspirate has higher sensitivity than sputum

›Characteristic "pilot wheel" or "ship wheel" multi-budding yeast

›Yeast size 15–30 micrometers; peripheral buds up to 60 micrometers

›Multiple peripheral buds on central mother cell = pathognomonic

›Rapid result available within hours

›Fungal culture

›Incubation at 25–30°C for 4–8 weeks required

›Slow growth; cultures may be negative in up to 30% of cases

›Biosafety level 3 precautions required for mycelial form

Serologic testing

›Immunodiffusion (ID) assay

›Reference standard serologic test for PCM diagnosis

›Specificity greater than 95%

›Sensitivity approximately 80%

›Quantitative titers correlate with disease severity

›Titers monitored every 3–6 months as treatment response marker

›Negative or significantly decreased titer = serologic cure

›Complement fixation (CF) assay

›Alternative serologic method at reference laboratories

›Titers also used for treatment response monitoring

›Less widely available than immunodiffusion

›PCR-based detection

›Available in some reference centers; not yet fully standardized

›Not commercially available as point-of-care test

›Useful in seronegative immunocompromised patients

06Diagnostic Tests/dt66

Scoring Systems

›PCM severity classification (clinical utility)

›Mild-to-moderate disease criteria

›Localized pulmonary or mucosal involvement

›Stable vital signs and ability to tolerate oral medications

›Normal or mildly elevated inflammatory markers

›Severe disease criteria

›Disseminated multiorgan involvement (CNS, adrenal, bone marrow)

›Respiratory failure or hemodynamic instability

›Inability to tolerate oral medications

›Immunocompromised host (HIV, transplant)

›Pediatric prognostic markers (Lancet ID 2017)

›Poor prognosis associated features

›Eosinophilia > 25,000 cells per mm3

›Hepatosplenomegaly (86% of fatalities vs. 22% survivors)

›Lymph node fistulization (27% of pediatric cases)

›Mortality without treatment: uniformly fatal in juvenile form

MRI

›Brain MRI indications

›Any neurological symptom: headache, seizures, focal deficits

›Granulomatous lesions with ring-enhancement on T1 post-gadolinium

›T2 hyperintense lesions in white matter

›Meningeal enhancement suggesting leptomeningeal disease

›Can mimic TB meningitis radiographically

›Hydrocephalus from ventricular obstruction

›Requires neurosurgical consultation

›Spinal MRI indications

›Back pain with neurological deficits

07Disposition/dispo40

Admission criteria

›Indications for inpatient admission

›Severe or disseminated disease requiring IV amphotericin B

›CNS involvement with neurological deficits

›Respiratory failure or hemodynamic instability

›Adrenal crisis or suspected adrenal insufficiency

›Requires IV steroid replacement and monitoring

›Acute/juvenile form with systemic toxicity

›High mortality without prompt treatment

›Inability to tolerate oral medications

›Significant malnutrition or dehydration requiring IV support

ICU criteria

›ICU-level care indications

›Ventilatory failure requiring mechanical ventilation

›Bilevel or HFNC failure

›Refractory shock despite fluid resuscitation

›Vasopressor requirement (norepinephrine)

›Adrenal crisis with hemodynamic compromise

›Rapidly progressive juvenile form with multi-organ failure

Discharge criteria

›Criteria for outpatient management

›Mild-to-moderate disease with stable vital signs

›Tolerating oral itraconazole or TMP-SMX

›No CNS or adrenal involvement

›Reliable access to follow-up

›Infectious disease clinic within 2–4 weeks

›Pharmacy access for long-duration antifungal therapy

›Capacity to understand and adhere to treatment

08Treatment/t77

Severe and disseminated disease

›Amphotericin B induction (IV, 2–4 weeks)

›Amphotericin B deoxycholate

›0.7–1.0 mg/kg/day IV infused over 4–6 hours

›Premedicate with acetaminophen and diphenhydramine to reduce infusion reactions

›Liposomal amphotericin B (preferred if renal impairment or toxicity)

›3–5 mg/kg/day IV

›Less nephrotoxicity; equivalent or superior efficacy

›Monitoring during amphotericin B

›Daily serum creatinine, potassium, magnesium

›Potassium replacement target 4.0 mmol/L

›Magnesium replacement target 0.85 mmol/L

›Step-down to oral itraconazole after clinical stabilization

›Transition when patient tolerating oral intake

›Itraconazole 200–400 mg daily for 12–18 months total

Mild-to-moderate disease (first-line)

›Itraconazole oral therapy

›Itraconazole 200 mg PO once daily for 9–18 months

›Efficacy rate 86–91% (superior to TMP-SMX)

›Time to clinical cure approximately 105 days vs. 159 days with TMP-SMX

›Administration requirements

›Take with food or acidic beverage (cola) to enhance absorption

›Avoid concurrent antacids, proton pump inhibitors, or H2 blockers

›Capsule formulation less reliably absorbed than solution

›Drug interactions (CYP3A4 inhibition)

›Warfarin: INR elevation; monitor closely

›Statins: increased myopathy risk; suspend simvastatin/lovastatin

›Calcium channel blockers: additive hypotension risk

›Therapeutic drug monitoring

›Trough target 0.5–4.0 mg/L

›Check 2 weeks after initiation; only 44% achieve therapeutic range with capsules

›Itraconazole treatment endpoints

›Clinical resolution of signs and symptoms

›ESR normalization

›Immunodiffusion titer negative or significantly decreased

›Do not discontinue based on clinical improvement alone

›Serologic cure required before stopping

Mild-to-moderate disease (alternative/second-line)

›TMP-SMX (trimethoprim-sulfamethoxazole) oral therapy

›TMP-SMX 800 mg/160 mg (one DS tablet) PO twice daily for 18–24 months

›Adequate response in approximately 74% with good adherence

›Fungistatic only; longer treatment duration required vs. itraconazole

›Cure rate 51.3% vs. 86.4% for itraconazole at equivalent time points

›Advantages over itraconazole

›Lower cost; greater availability in endemic regions

›Safer in pregnancy (avoid in first trimester and near term)

›Monitoring

›Renal function and CBC every 2–3 months (bone marrow suppression risk)

›Maintain adequate hydration to reduce crystalluria risk

CNS disease

›Voriconazole for CNS paracoccidioidomycosis

›Voriconazole 6 mg/kg IV every 12 hours x 2 doses (loading), then 4 mg/kg IV every 12 hours

›Superior CNS penetration vs. itraconazole

›Step-down to voriconazole 200–300 mg PO twice daily when clinically stable

›Treatment duration 6–12 months for CNS disease

›Monitor LFTs every 4–6 weeks (hepatotoxicity)

›Visual disturbances are common adverse effect (monitoring required)

›Fluconazole alternative for CNS disease (if voriconazole unavailable)

›Fluconazole 400–800 mg PO daily

›Less potent than voriconazole for Paracoccidioides

Adrenal insufficiency management

›Acute adrenal crisis treatment

›Hydrocortisone 100 mg IV push immediately

›Follow with hydrocortisone 50 mg IV every 6 hours for 24–48 hours

›Taper to physiologic replacement as clinical status improves

›Isotonic saline 1–2 L IV over first hour for volume resuscitation

›Dextrose correction for hypoglycemia (50 mL of 50% dextrose IV)

›Chronic adrenal replacement

›Hydrocortisone 15–25 mg PO daily in divided doses (morning-dominant)

›Fludrocortisone 0.05–0.1 mg PO daily for mineralocorticoid replacement

›Target sodium, potassium, and blood pressure normalization

Antifungal treatment failure and relapse

›Relapse management

›Relapses may occur up to 5 years after apparent cure

›Reassess adherence, drug levels, and absorption

›Repeat serology and culture

›Switch from TMP-SMX to itraconazole if relapse on TMP-SMX

›Voriconazole for itraconazole-refractory cases

›Supportive measures

›Nutritional support (malnutrition worsens outcomes)

›Dietitian referral for severe malnutrition

›Alcohol cessation (hepatotoxicity risk with azoles)

›Smoking cessation (pulmonary fibrosis risk reduction)

09Special Populations/sp60

Pregnancy

›Antifungal safety in pregnancy

›Itraconazole is CONTRAINDICATED in pregnancy

›Teratogenic in animal studies; Category D/X

›Avoid throughout pregnancy and when breastfeeding

›TMP-SMX preferred for mild-to-moderate PCM in pregnancy

›Avoid in first trimester (folate antagonism; risk of neural tube defects)

›Avoid near term (neonatal hyperbilirubinemia, kernicterus risk)

›Folic acid supplementation mandatory with TMP-SMX

›Amphotericin B for severe PCM in pregnancy

›Considered relatively safe (FDA Category B)

›Deoxycholate or liposomal formulation; neonatal renal monitoring

›Pregnancy-specific considerations

›PCM can reactivate during pregnancy due to immunologic changes

›Hormonal protection against PCM in premenopausal women is progesterone-dependent

›Multidisciplinary management: ID, obstetrics, and neonatology

›Monitor fetal growth and neonatal status if treatment required

›Breastfeeding: TMP-SMX excreted in breast milk; risk-benefit discussion required

Geriatric

›Age-related pharmacokinetic changes

›Itraconazole absorption reduced with achlorhydria (common in elderly)

›Solution formulation preferred over capsules

›Check for concurrent PPI or H2 blocker use (reduces absorption)

›Renal function decline affects TMP-SMX dosing

›Dose reduction required for eGFR < 30 mL/min/1.73m2

›Avoid TMP-SMX if eGFR < 15 mL/min/1.73m2

›Amphotericin B nephrotoxicity risk increased in elderly

›Liposomal formulation preferred

10Background/b81

Epidemiology

›Geographic distribution

›Strictly endemic to Latin America

›Brazil accounts for approximately 80% of all global cases

›Also endemic in Colombia, Venezuela, Argentina, Paraguay, and Ecuador

›Absent from Caribbean islands and Chile (altitude or climate barrier)

›Estimated annual incidence: 1–3 cases per 100,000 in endemic regions

›Brazil alone reports approximately 8,000 new cases per year

›Accounts for approximately 200 deaths annually in Brazil

›Affected populations

›Chronic adult form: males aged 30–60 years predominantly

›Male-to-female ratio 13–20:1 in chronic form

›Rural agricultural workers most affected

›Juvenile form: children and adolescents of both sexes

›Represents approximately 10% of all PCM cases

›Higher case fatality rate than adult chronic form without treatment

›Migration and urbanization expanding geographic risk

›Cases now reported in non-endemic countries (travelers, immigrants)

›Classified as a neglected tropical disease

›Listed among neglected endemic mycoses by WHO

›Significant socioeconomic burden in endemic regions

Pathophysiology

›Causative organisms

›Paracoccidioides brasiliensis (complex of cryptic species)

›Major cause of PCM globally; multiple phylogenetic clades

›Paracoccidioides lutzii

›Predominant in Brazilian Central-West and Amazon regions

›May have distinct clinical features

›Infection mechanism

›Inhalation of airborne conidia or hyphal fragments from soil

›Fungi is thermally dimorphic: mycelium at 25°C, yeast at 37°C

›Conidia transform to yeast form upon reaching alveoli

›No person-to-person transmission

›No isolation required for hospitalized patients

›Primary infection results in pulmonary focus

›Most infections are subclinical and self-limited in immunocompetent hosts

›Reactivation of latent infection can occur decades later

›Host immune response and disease forms

›Granulomatous inflammation is the key host defense

›Activated macrophages and CD4+ T cells required for containment

›Th1 response (IFN-gamma, TNF-alpha) confers protection

›Th2 skewing associated with progressive disseminated disease

›Sex hormones influence susceptibility

›Estradiol inhibits the mycelium-to-yeast conversion in vitro

›Explains dramatic male predominance in chronic form

›Adrenal gland tropism

›Bilateral adrenal gland involvement in up to 50% of autopsied cases

›Granulomatous replacement causes Addison's syndrome

›Tissue pathology

›Characteristic multi-budding yeast in tissue ("pilot wheel" appearance)

›15–30 micrometers diameter; up to 60 micrometers

›Multiple peripheral buds on central mother cell

›Granulomatous inflammation with giant cells

›Progressive fibrosis in chronic disease

›Pulmonary fibrosis, microstomy, and CNS scarring as sequelae

Therapeutic Considerations

›Antifungal selection principles

›Itraconazole is the standard first-line agent for non-severe PCM

›Fungicidal; superior clinical and serologic cure rates vs. TMP-SMX

›Class I recommendation (Lancet ID Global Guidelines 2021)

›TMP-SMX is fungistatic; requires longer treatment duration

›Adequate alternative when itraconazole unavailable or contraindicated

›Inferior cure rate (51.3% vs. 86.4%) at equivalent timepoints

›Amphotericin B reserved for severe/disseminated and pregnancy

›Liposomal formulation preferred for reduced nephrotoxicity

›Voriconazole for CNS disease or refractory cases

›Superior CNS penetration; considered off-label but guideline-supported

›Treatment duration principles

›Never stop based on clinical improvement alone

›Serologic cure (negative or markedly reduced immunodiffusion titer) required

›ESR normalization as secondary endpoint

›Duration varies by disease severity and agent

›Itraconazole: 9–18 months for chronic form; 12–18 months for severe

›TMP-SMX: 18–24 months minimum

›Relapse risk requires long-term surveillance post-treatment

›Monthly serologic monitoring recommended for 2 years after stopping

›Sequelae prevention and management

›Pulmonary fibrosis: early treatment initiation may reduce extent

›Baseline and annual pulmonary function testing

›Smoking cessation counseling

›Microstomy (reduced oral aperture) from orofacial fibrosis

›ENT and oral surgery referral for reconstructive planning

›Addison's syndrome: lifelong steroid replacement if adrenal destruction occurs

›Neurological sequelae: rehabilitation referral for persistent deficits

11Patient Discharge Instructions/pdi30

copy discharge instructions

›Diagnosis and disease explanation

›Paracoccidioidomycosis (PCM) is a fungal infection caused by Paracoccidioides

›Endemic to South and Central America; acquired by inhaling soil fungi

›Not contagious from person to person

›This infection requires months to years of antifungal treatment

›Do not stop your medication early, even if you feel better

›Medication instructions

›Itraconazole: take every day with a full meal or cola drink

›Avoid antacids (Tums, Maalox), omeprazole, or ranitidine — these reduce absorption

›Do not drink alcohol during treatment (liver damage risk)

›Take itraconazole at the same time each day

›TMP-SMX: take twice daily with plenty of water

›Report rash, severe stomach pain, or unusual bruising immediately

›Steroid replacement (if prescribed): never skip a dose

›Carry a medical alert card or bracelet indicating adrenal insufficiency

›Double dose during any illness, fever, or surgical stress (sick-day rules)

›Follow-up instructions

›Return to clinic in 2–4 weeks for blood tests and symptom check

›Liver blood tests and fungal antibody levels will be monitored

›Treatment will last at least 9–18 months; follow-up is essential throughout

›Do not miss appointments — stopping treatment too early causes relapse

›Return to emergency department immediately for

›Worsening shortness of breath or coughing up blood

›Severe mouth pain or inability to swallow

›New or worsening headache, seizure, confusion, or weakness

›Fainting, severe dizziness, or very low blood pressure

›Yellowing of skin or eyes (jaundice) suggesting liver problems

12References/r32

Guidelines and key sources

›Thompson GR, Le T, Chindamporn A, et al.

›Global Guideline for the Diagnosis and Management of the Endemic Mycoses

›The Lancet Infectious Diseases 2021

›https://pubmed.ncbi.nlm.nih.gov/34364529

›Hahn RC, Hagen F, Mendes RP, et al.

›Paracoccidioidomycosis: Current Status and Future Trends

›Clinical Microbiology Reviews 2022

›https://pubmed.ncbi.nlm.nih.gov/36074014

›Queiroz-Telles F, Fahal AH, Falci DR, et al.

›Neglected Endemic Mycoses

›The Lancet Infectious Diseases 2017

›https://pubmed.ncbi.nlm.nih.gov/28774696

›de Siqueira NPL, da Silva Pinto G, Ueda CY, et al.

›Paracoccidioidomycosis in Childhood and Adolescence: Clinical-Epidemiological Review of South American Cases (1970–2023)

›Mycopathologia 2025

›https://pubmed.ncbi.nlm.nih.gov/41298938

Comparative treatment trials

›Cavalcante Rde S, Sylvestre TF, Levorato AD, et al.

›Comparison Between Itraconazole and Cotrimoxazole in the Treatment of Paracoccidioidomycosis

›PLoS Neglected Tropical Diseases 2014

›https://pubmed.ncbi.nlm.nih.gov/24743230

›Borges SR, Silva GM, Chambela Mda C, et al.

›Itraconazole vs. Trimethoprim-Sulfamethoxazole: A Comparative Cohort Study of 200 Patients With Paracoccidioidomycosis

›Medical Mycology 2014

›https://pubmed.ncbi.nlm.nih.gov/24577007

›Kruschewsky WLL, de Freitas VLT, Taborda M, et al.

›Therapeutic Drug Monitoring of Itraconazole in Endemic Paracoccidioidomycosis: Real-World Data

Evidence & Review

Evidence & Review