Jennifer Pichay-Alvarado, MD, DPPS

Fever

Elevation of body temperature exceeding the normal daily variation

and occurs in conjunction with an

increase in the hypothalamic set point

(from 37C to 39C)

18 to 40 years old (mean oral temperature = 36.8C+ 0.4C)

Maximum oral temp 37.2C (6am) 37.7C (4pm)

Rectal = 0.4C higher than oral temp

Tympanic membrane = 0.8C lower than rectal temp

Axillary = 0.3-0.6C lower than oral temp

Definition:

Fever of Unknown Origin

Temperatures of >38.3C on several occasions

Duration of fever of >3 weeks

Failure to reach a diagnosis despite 1 week of in-patient investigation

Petersdorf and Beeson

1961

Classification:

better accounts for non endemic and emerging diseases, improved diagnostic technologies and adverse reactions to new therapeutic interventions

1. Classic FUO

2. Nosocomial FUO

3. Neutropenic FUO

4. FUO associated with HIV infection

Durack and Street Revised system for classification

Classic FUO

3 OPD visits 3 days in the hospital without elucidation of a

cause

1 week of intelligent and invassive ambulatory investigation

Causes : infection (bacterial, viral, protozoal or fungal)

Neoplasms

Non-Infectious inflammatory diseases

systemic rheumatologic or vasculitic disease (polymyalgia rheumatica, lupus, Stills disease)

Granulomatous diseases (Sarcoidosis, Crohns disease and granulomatous hepatitis

Multisystem diseases frequent cause in elderly patients (giant cell arteritis) 15-20% (>50 years old)

Tuberculosis most common infection causing FUO in elderly

Colon cancer most important cause of FUO with malignancy in elderly

Miscellaneous drug fever, pulmonary embolism, factitious fever, hereditary periodic syndromes (familial

mediterranean fever, hyper IgD syndrome, TNF receptor-

associated periodic fever (TRAPS or hibernian fever),

familial cold urticaria and Muckle-Wells syndrome,

Congenital lysosomal storage diseases (Gauchers and

Fabrys disease

Causes of FUO Lasting > 6 months

No fever 27%

Non identified 19%

Miscellaneous 13%

Factitious 9%

Granulomatous hepatitis 8%

Neoplasm 7%

Stills disease 6%

Infection 6%

Collagen vascular disease 4%

Familial Mediterranean fever 3%

R. Aduan et al 1978

NIH 1961-1977 (347 px)

Nosocomial FUO

Patients susceptibility

Potential complications of hospitalization

Surgical or procedural field place to begin a directed physical and laboratory exam abscesses, hematomas,

infected foreign body

50% infected

IV lines, septic phlebitis, prostheses

Focus on sites where occult infections (best approach)

sinuses intubated patients

Prostatic abscess catheterized patients

25% non infectious cause

Acalculous cholecystitis

Deep vein thrombophlebitis

Pulmonary embolism

Drug fever

Transfusion reaction

Alcohol/drug withdrawal

Adrenal insufficiency

Thyroiditis

Pancreatitis

Gout

Pseudogout

Management:

Meticulous PE

Focused diagnostic techniques

Blood, wound and fluid cultures

CT scan, ultrasound

20% no diagnosis

Change IV lines

Drugs stopped for 72 hours

Start empirical therapy

Vancomycin methicillin resistant S. aureus

Piperacillin/Tazobactam, Ticarcillin/Clavulanate, Imipenem or Meropenem broad spectrum G(-)

Neutropenic FUO

Neutropenic patients susceptible to focal bacterial and fungal infections, to bacteremic infections, to infections involving catheters (septic thrombophlebitis) and to perianal infections (candida and aspergillus)

HSV and CMV infections are common Short duration of illness Catastrophic if untreated 50% - 60% febrile neutropenics infected 20% bacteremic Severe mucositis, quinolone prophylaxis, colonization with

methicillin resistant S. aureaus, obvious catheter-related infection or hypotension use Vancomycin plus Ceftazidime, Cefepime or Carbapenem with or without aminoglycoside -provide empirical coverage (bacterial sepsis)

HIV-associated FUO

HIV ifection cause of fever

Causes

M. avium or intracellulare, NHL

Tuberculosis

Toxoplasmosis

CMV infection

Pneumocystis infection

Salmonellosis

Cryptococcosis

Histoplasmosis

Strongyloidiasis

NHL, drug fever

Diagnosis

Blood cultures

Liver, bone marrow and lymph node biopsies

Chest CT scan

Serologic tests cryptococcal antigen; 67Ga scan (Pneumocystis pulmonary infection)

>80% HIV infected patients infectious etiology

Drug fever and lymphoma important consideration

Treatment

Age and physical state elderly (trial of empirical therapy early)

Continue observation and examination

Avoid shotgun empirical therapy

Vital sign instability and neutropenia indication for empirical therapy (Fluoroquinolone plus Piperacillin)

TST + = therapeutic trial for TB up to 6 weeks, if still with fever = alternative diagnosis

Glucocorticoids = temoral arteritis, polymyalgia rheumatica and granulomatous hepatitis

Cochicine = familial mediterranean fever

*No underlying source of FUO after

>6 months = good prognosis

Debilitating symptoms = treated with NSAIDs Glucocorticoids = last resort Initiation of empirical therapy = not the end of

diagnostic work ups

Continue thorough reexamination and evaluation

Patience, compassion, equanimity, vigilance and intellectual flexibility = indispensable attributes for the clinician in dealing successfully with FUO

Fungal Infections

HISTOPLASMOSIS

Histoplasma capsulatum

Most prevalent endemic mycosis in North America

Inhalation of microconidia

Clinical Manifestation:

Asymptomatic to life threatening illness

Symptoms appear 1-4 weeks after exposure

Flu-like illness (fever, chills, sweats, headache, myalgia, anorexia, cough, dyspnea and chest pain)

Chest radiograph pneumonitis with hilar or mediastinal adenopathy

Rheumatologic symptoms of arthralgia or arthritis, associated with erythema nodosum 5%-10% cases

Pericarditis may also develop

Hilar and mediastinal lymphnodes undergo necrosis and coalesce forming large mediastinal mass

compressing great vessels, proximal airways and

esophagus

Necrotic lymphnodes may rupture and create bronchoesophageal fistula

Progressive Disseminated Histoplasmosis(PDH) immunocompromised patient 70% cases

Risk factors : AIDS, extremes of age, use of immunosuppressive medications (Prednisone,

Methotrexate, anti TNF alpha agents)

Spectrum of PDH :

Acute -rapidly fatal course (with diffuse intersttial or reticulonodular lung infiltrates causing Respiratory failure, shock, coagulopathy, Multiorgan failure

Subacute focal organ distribution (fever, weight loss, hepatosplenomegaly, meningitis, focal brain lesions, ulcerations of oral mucosa, GI ulcerations and adrenal insufficiency)

Chronic cavitary histoplasmosis

smokers with structural lung disease (productive cough, dyspnea, low grade fever, night sweats and weight loss)

CXR UL infiltrates, cavitation, pleural thickening

Slowly progressive if untreated

Fibrosing mediastinitis

serious complication but uncommon

1/3 cases fatal

Unilateral or bilateral involvement (worst prognosis)

SVC syndrome, pulmonary vessel obstruction and airway obstruction

Recurrent pneumonia, hemoptysis or respiratory failure

Broncholithiasis

in healed histoplasmosis, calcified mediastinal nodes or lung parenchyma may erode through the walls of

airway causing hemoptysis

African histoplasmosis

H. capsulatum var duboisii

Skin and bone involvement

Diagnosis:

Fungal Culture gold standard

Result up to 1 month

(-) for less severe cases

75% (+) PDH and Chronic pulmonary histoplasmosis

BAL fluid, BM aspirates and blood

Sputum or bronchial washing (+) chronic pulmonary

histoplasmosis

Fungal stains of cytopathology or biopsy materials

Histoplasma antigen in body fluids

Useful in the diagnosis of PDH

>95% sensitive (PDH)

80 % sensitive (Acute pulmonary histoplasmosis)

Serologic tests

Immunodiffusion and Compliment fixation

Useful for diagnosis of self limited histoplasmosis and chronic pulmonary histoplasmosis

1 month for antibody production

Limitations : insensitive in early infection and immunosuppressed patients, persistence of detectable antibody several years after infection

Treatment:

Acute pulmonary, moderate to severe illness with diffuse infiltrates and/or hypoxemia

Lipid Amphothericin B (3-5mg/kg/day)+glucocorticoids for 1-2 weeks; then Itraconazole(200mg BID) for 12 weeks

Mild cases recover without therapy but may give Itraconazole if no improvement

Chronic/cavitary pulmonary

Itraconazole(200mg BID or QID) for atleast 12 months

Continue therapy until xray show no improvement

Monitor relapse after treatment stopped

Progessive disseminated

Lipid Amphothericin B (3-5mg/kg/day) for 1-2 weeks then Itraconazole (200mg BID) for atleast 12 months

Chronic maintenance therapy necessary if degree of immunosuppression cannot be reduced

CNS

Liposomal Amphothericin B (5mg/kg/day) for 4-6 weeks then Itraconazole (200mg BID or TID) for atleast 12 months

Longer course of lipid AmB recommended due to relapse

Continue Itraconazole until CSF or CT abnormalities clear

Posaconazole, Voriconazole and Fluconazole alternative for Itraconazole

Monitor blood levels of Itraconazole 2-10ug/ml (target concentration)

Duration of treatment

APH 6-12 weeks

PDH - > 1 year

Monitor antigen levels in urine and serum during and for atleast 1 year after therapy for PDH

Stable or rising antigen level treatment failure or relapse

Maintenance therapy with Itraconazole not required

a. for patients who respond well to antiretroviral therapy

b. CD4+ T cell counts of atleast 150/uL (preferably >250/uL)

c. Completed atleast 1 year of Itraconazole therapy

d. Exhibit neither clinical evidence of active histoplasmosis

nor antigenutria level of > 4ng/ml

e. Patients receiving immunosuppressive treatment

Fibrosing mediastinitis (chronic fibrotic reaction to past mediastinal histoplasmosis rather than active infection)

does not respond to antifungal therapy

COCCIDIOIDOMYCOSIS

Valley fever

Dimorphic soil-dwelling fungi Coccidioides

C. immitis and C. posadasii

60% asymptomatic

40% pulmonary infection

Cough, fever and pleuritic chest pain

Risk of symptomatic illness increases with age

Commonly misdiagnosed as Community acquired bacterial pneumonia

Cutaneous manifestation

Toxic erythema maculopapular rash

Erythema nodosum lower extremities

Erythema multiforme necklace distribution

Arthralgia and arthritis may develop

Primary pulmonary coccidioidomycosis history of night sweats, profound fatigue, peripheral blood

eosinophilia and or hilar or mediastinal

lymphadenopathy(CXR)

10% develop pleural effusion (associated with

pulmonary infiltrate on same side, cellular content

mononuclear)

Resolves without sequela in several weeks

Pulmonary nodules residua of primary pneumonia

(single, located at the upper lobes,

Pulmonary cavities

thin walled shell which occur when nodule extrude its

contents into the bronchus

Associated with persistent cough, hemoptysis and

pleuritic chest pain

Pyopneumothorax when cavity rupture into pleural space (rare)

Acute dyspnea

Collapsed lung with pleural air fluid level

Chronic or persistent pulmonary coccidioidomycosis

Prolonged fever, cough and weight loss

Scarring, fibrosis and cavities (CXR)

< 1%

Primary diffuse coccidioidal pneumonia

Diffuse reticulonodular pulmonary process (CXR)

Associated with dyspnea and fever

Intense environmental exposure or profound suppressed cellular immunity (AIDS), unrestrained fungal growth frequently associated with fungemia

Clinical dissemination outside thoracic cavity occurs < 1%

Risk factors :mostly males, African-American or Filipino ancestry, patients with depressed cellular immunity, women on 2nd and 3rd trimester

Common sites : skin, bone, joint, soft tissue and meninges

Follow symptomatic and asymptomatic pulmonary infection, evident within first few months after primary pulmonary infection

Meningitis

fatal if untreated

Persistent headache, lethargy, confusion, (+) nuchal

rigidity

CSF exam: lymphocytic pleocytosis, profound

hypoglycorrhachia and elevated proten levels, CSF

eosinophilia

With or without appropriate therapy may develop

hydrocephalus (marked decline in mental status ften

with gait disturbances)

Diagnosis:

Serology

a. Tube Precipitin and Complement fixation assay

b. Immunodiffusion and Enzyme immunoassay detect IgG and IgM antibodies

TP and IgM antibodies found in serum soon after infection and persist for weeks (not useful for gauging disease progression and not found in CSF

CF and IgG occur later in the course of the disease and persist longer than TP and IgM antibodies

Rising CF titers associated with clinical progression and the presence of CF antibody in CSF (meningitis)

Antibodies disappear overtime in person whose clinical illness resolves

Coccidioidal EIA

Frequently used as screening tool

Culture

Coccidioides grows within 3-7 days at 37C artificial

media including blood agar

Sputum, other respiratory fluid and tissues

Stains

Hematoxylin Eosin

Papanicolau

Gomori methenamine silver

Test for antigenuria and antigenemia

False positive result

Treatment:

Asymptomatic 60% none

Primary pneumonia (focal) 40% - none (most cases)

Diffuse pneumonia

Duration of treatment is based on:

a. resolution of signs and symptoms of the lesion

b. Significant decline in serum CF antibody titer

Usually continued for atleast several years

Relapse 15-30% once therapy discontinued

80% relapse (meningitis) life long therapy recommended

Triazole therapy failure intrathecal or intraventricular Amphothericin B

Hydrocephalus CSF shunting plus Antifungal therapy

Prevention:

Avoid direct contact with uncultivated soil or visible dust with soil

Prophylactic antifungal therapy appropriate in patients with:

a. active or recent coccidioidomycosis

b. About to undergo allogeneic solid-organ

transplantation

Give antifungal therapy to patients with history of active coccidioidomycosis or positive coccidioidal

serology in whom therapy with TNF alpha antagonist

is being initiated

BLASTOMYCOSIS

Systemic pyogranulomatous infection involving primarily the lungs

Inhalation of conidia

Blastomyces dermatitidis

Risk factors:

a. Middle aged man

b. Outdoor occupations

Grows as microfoci in the warm, moist soil of wooded areas rich in organic debris

Exposure to soil (work or recreation)

Clinical manifestation:

Acute pulmonary infection

Diagnosed in association with point source outbreaks

abrupt onset of fever, chills, pleuritic chest pain,

arthralgias and myalgias

Non productive cough purulent

CXR alveolar infiltrates with consolidation

Chronic indolent pneumonia

fever, weight loss, productive cough and hemoptysis

CXR alveolar infiltrates with or without cavitation, mass

lesions (mimic bronchogenic ca and fibronodular

infiltrates)

Respiratory failure(ARDS) associated with miliary disease or diffuse pulmonary infiltrates more common among immunocompromised patients

Mortality rates > 50%

Deaths occur within first few days of therapy

Skin disease most common extrapulmonary manifestation

Verrucous - most common

Ulcerative

Osteomyelitis

of B.dermatitidis infection

Vertebra, pelvis, sacrum, skull,ribs or long bones

Presents with contiguous soft tissue abscesses or chronic draining sinuses

Prostate and epididymis involvement in males

CNS involvement

< 5% cases immunocompetent

40% AIDS

Presents as brain abscess

Cranial or spinal epidural abscess

Meningitis

Diagnosis:

Culture

Definitive diagnosis

Specimen: sputum, pus or biopsy material

Visualization of broad based budding yeast

Presumptive diagnosis

Serology limited due to cross reactivity

Blastomyces antigen assay detects antigen in urine and serum

Urine more sensitive

Useful in monitoring patients during therapy or for

early detection of relapse

Molecular identification techniques DNA probe

hybridization supplement traditional mtds

Treatment:

Immunocompetent/Life threatening disease

Pulmonary LipidAmB (3-5mg/kg) qd or deoxycholate AmB(0.7-1 mg/kg qd

Itraconazole 200-400mg/d (once

stabilized) alternative

Disseminated

CNS Lipid AmB or deoxycholate AmB, Fluconazole 800 mg/d intolerant with full

course AmB alternative

Non CNS Lipid AmB or deoxycholate AmB, Itraconazole 200-400mg/d (once stabilized)

Immunocompetent/Non life threatening disease

Pulmonary or disseminated (non CNS)

Itraconazole or LipidAmB or deoxycholate AmB

Fluconazole 400-800mg/d or Ketoconazole

Immunocompromised

All infections

Lipid AmB or deoxycholate AmB

Itraconazole 200-400 mg/d (non CNS once

clinically improved)

CRYPTOCOCCOSIS

Cryptococcus neoformans and C. gattii

First described in 1890s, acquired by inhalation of aerosolized infectious particle

Meningoencephalitis and pneumonia

Skin and soft tissue infection

At risk : hematologic malignancies, solid organ transplant recipient with ongoing immunosuppressive treatment, glucocorticoid therapy and with advanced HIV infection and CD4+ T lymphocyte counts 600,000 deaths annually

C. neoformans soil contaminated avian excreta, shaded and humid soil contaminated with pigeon droppings

C. gattii eucalyptus tree

Clinical manifestations:

CNS involvement chronic meningitis (headache, fever, lethargy, sensory deficits, memory deficits,

cranial nerve paresis, vision deficits and meningismus

Pulmonary cough, increased sputum production and chest pain

Crytococcomas C. gattii, granulomatous pulmonary masses

Skin lesion common in disseminated cases, papules, plaques, purpura, vesicles, tumor like lesions and

rashes

AIDS and solid organ transplant patients lesions of cutaneous crytococcosis resemble molluscum

contagiosum

Diagnosis:

CSF India Ink Examination

useful rapid diagnostic technique

(-) low fungal burden

Culture

CSF

Crytococcal antigen (CRAg) detection

CSF and blood

Based on serological detection of polysaccharide

Sensitive and specific

less useful in pulmonary disease

Treatment:

Pulmonary Fluconazole (200-400mg/d) 3-6 months

Extrapulmonary without CNS involvement same regimen, AmB .5-1mg/kg daily 4-6 weeks (severe cases)

CNS involvement without AIDS or obvious immune impairment AmB(.5-1mg/kg daily induction phase,

followed by Fluconazole (400mg/d) during

consolidation phase

Cryptococcal meningoencephalitis without concomitant immunosuppressive condition AmB plus

flucytosine (100mg.kg) daily for 6-10 weeks,

alternatively AmB plus flucytosine daily for 2 weeks

then with Fluconazole (400mg/d) atleast 10 weeks

Prognosis and Complications:

High rate of morbidity and death

Extent and duration of underlying immunologic deficits - most important prognostic factor

Curable with antifungal therapy no apparent immunologic dysfunction

Severe immunosuppression antifungal induce remission, maintained with life long suppressive

therapy

Survival period

AIDS -

CNS poor prognostic marker

(+) CSF assay for yeast cells by initial india ink exam

High CSF pressure

Low CSF glucose levels

Low CSF pleocytosis

Prevention:

No vaccine

Primary prophylaxis with Fluconazole 200mg/day

Advanced HIV infection

CD4+ T lymphocyte

CANDIDIASIS

Candida species (albicans, guilliermondii,krusei, parapsilopsis, tropicalis, kefyr, lusitaniae, dubliniensis, and glabrata)

Inhabit GIT (mouth and oropharynx), female genital tract, skin

Most common nosocomial pathogen

Predisposing factors for hematogenous spread

Antibacterial agents, respirators

Indwelling intravascular catheter, neutropenia

Hyperalimentation fluids,abdominal and thoracic surgery

Indwelling urinary catheter, cytotoxic chemotherapy

IV glucocorticoids

Immunosuppressive agents for organ transplantation

Severe burns

Low birth weight illicit IV drugs use

HIV patients

DM (mucocutaneous)

Women receiving antibacterial agent (Vaginal

candidiasis)

Clinical manifestations:

Mucocutaneous candidiasis

Thrush

white, adherent, plainless, discrete or confluent patches

in the mouth, tongue, or esophagus with fissuring at

corners of mouth

Points of contact with dentures

Vulvovaginal candidiasis

Pruritus, pain and vaginal discharge (thin , whitish

curds)

Other candidiasis

Paronychai- painful swelling at the nail-skin interface

Onychomycosis fungal nail infection

Intertrigo erythematous irritation with redness and pustules in the skin folds

Balanitis erythematous pustular infection of glans penis

Erosio interdigitalis blastomycetica infection between digit of hands or toes

Folliculitis with pustules developing most frequently in the area of beard

Perianal candidiasis pruritic erythematous pustular infection surrounding the anus

Diaper rash erythematous pustular perineal infection (infants)

Generalized disseminated cutaneous candidiasis occurs primarily in infants, widespread eruption over trunk, thorax and extremities

Chronic mucocutaneous

heterogenous infection of hair, nails, skin and mucous membranes persists despite intermittent therapy

infancy or within 1st 2 decades of life

Mild and limited to specific area of skin or nails

Candida granuloma

severely disfiguring form, exophytic outgrowths on the

skin, associated with immunologic dysfunction

APECED syndrome

autoimmune polyendocrinopathy-candidiasis-

ectodermal dystrophy

due to mutation in autoimmune regulator gene

most prevalent among Finns, Iranian, Jews, Sardinians,

northern Italians and Swedes

Hypoparathyroidism, Graves disease

Adrenal insufficiency, autoimmune thyroiditis

Chronic active hepatitis, alopecia, juvenile onset

pernicious anemia, malabsorption, primary

hypogonadism

Dental enamel dysplasia

Vitiligo

Pitted nail dystrophy

Calcification of tympanic membranes

Deeply invasive candidiasis

Result of hematogenous seeding of various organs as a complication of candidemia

Brain, chorioretina, heart and kidneys (most common)

Liver and spleen (less common)

Endocrine gland, pancreas, heart valves (native or prosthetic), skeletal muscle, joints, bone and meninges

Skin (macronodular lesion)

Diagnosis:

KOH pseudohyphae or hyphae

Grams stain, PAS or methenamine silver stain - inflammation

Presence of ocular or macronodular skin lesion highly suggestive of widespread infection of multiple deep

organs.

Prophylaxis:

Prophylactic Fluconazole ( 400mg/d) allogeneic stem cell transplants and high risk liver transplant recipients

Neutropenic patients Fluconazole (200-400mg/d); Lipid AmB (1-2mg/d); Caspofungin(50mg/d); Itraconazole(200mg/d); Posaconazole(200mg tid)

Surgical patients not always given prophylaxis

a. Low incidence of disseminated candidiasis

b. Suboptimal cost-benefit ratio

c. Increased resistance

Prophylaxis for oropharyngeal or esophageal candidiasis in HIV infected patients not recommended unless with frequent recurrences

ASPERGILLOSIS

All disease entities caused by any one of 35% pathogenic and allergenic species of Aspergillus

A. fumigatus most cases of invasive aspergillosis (chronic aspergillosis and most allergic syndromes

A. flavus prevalent in hospitals and cases of sinus and cutaneous infections and keratitis

A. niger invasive infection but more commonly colonizes respiratory tract and otitis externa

A. terreus invasive disease with poor prognosis

A. nidulans ninvasive infection, primarily with chronic granulomatous disease

Most commonly growing in decomposing plant materials and in bedding.

Found in indoor and outdoor air, on surfaces, and in water from surface reservoir

Incubation period : 2 90 days

Risk factors:

a. Profound neutropenia

b. Glucocorticoid use

c. Advanced HIV infection

d. Relapsed leukemia

Clinical Manifestations

Invasive pulmonary aspergillosis

Acute - < 1 month

Subacute 1-3 months

80% lung involvement

Fever, cough, chest discomfort, hemoptysis, shortness of

breath

Key to early diagnosis in at-risk patients:

a. High index of suspicion

b. Screening for circulating antigen (leukemia)

c. Urgent CT of the thorax

Invasive sinusitis

5-10% of cases

Leukemia and recipients of hematopoieticstem cell transplant

Fever, nasal or facial discomfort, blocked nose and bloody nasal discharge

Endoscopic exam of nosepale, dusky or necrotic looking tissue

CT or MRI of sinuses essential but does not distinguish invasive aspergillus sinusitis from

preexisting allergic or bacterial sinusitis early in the

disease process

Tracheobronchitis

Only airways are infected

Acute or chronic bronchitis to ulcerative or pseudomembranous tracheobronchitis

Common among lung transplant recipients

Obstruction with mucous plugs occurs in normal individual, persons with ABPS and

immunocompromised

Disseminated aspergillosis

Severely immunocompromised

Lungs to multiple organs brain (most often), skin, thyroid, bone, kidney, liver, git, eye, heart valves

Cutaneous lesions

Gradual clinincal deterioration over 1-3 days, low grade fever, mild sepsis and non specific abnormalities in lab test

Blood cultures almost always negative

Cerebral Aspergillosis

Devastating complication

Single or multiple lesions develop

Acute disease hemorrhagic infarction and abscess

Rare meningitis,mycotic aneurysm and cerebral granuloma

Mood changes, focal signs, seizures, decline in mental status

MRI most useful

Endocarditis

Prosthetic valve infections resulting from contamination during surgery

Native valve

Illicit IV drug use

Culture negative endocarditis with large vegetation most common presentation

Cutaneous aspergillosis

Erythematous or purplish nontender area that progresses to necrotic eschar

Direct invasion in neutropenic patients at IV catheter insertion site and burn patients

Chronic pulmonary aspergillosis

1 or more pulmonary cavities expanding over months or years in association with pulmonary symptoms and systemic manifestations

Fatigue, weight loss

Insidious onset

Systemic features more prominent than pulmonary

Cavities may have fluid level or a well formed fungal ball

Pericavitary infiltrates and multiple cavities are typical

Chronic fibrosing pulmonary aspergillosis unilateral or upper lobe fibrosis, end stage entity if CPA untreated

Aspergilloma

Fungal ball

20% residual pulmonary cavities > 2.5cm. Diameter

Cough, hemoptysis, wheezing and mild fatigue

Caused by A. fumigatus

A. niger in diabetics oxalosis with renal dysfunction

Life threatening hemoptysis complication

Fungal ball resolve spontaneously

Cavity may still be infected

Chronic sinusitis

Sinus aspergilloma

Maxillary sinus

Sinus cavity filled with fungal ball

Associated with upper-jaw root canal work and chronic bacterial sinusitis

90% CT scan focal hyperattenuation related to concretions

Removal of fungal ball curative

Chronic invasive sinusitis

Slowly destructive process

Ethmoid and sphenoid sinuses, any sinus

Imaging of cranial sinus opacification of sinus, local bone destruction and invasion of local structures

Chronic nasal discharge, blockage, loss of smell, persistent headache

Orbital apex syndrome blindness and proptosis

Facial swelling, Cavernous sinus thrombosis,

Carotid artery occlusion, pituitary fossa and brain and

skull base invasion

Chronic granulomatous sinusitis

Most commonly seen in the Middle East and India

Often cause by A. flavus

Presents late, with facial swelling and unilateral proptosis

Tissue necrosis with low grade mixed cell infiltrate typical

Allergic bronchopulmonary aspergillosis (ABPA)

Hypersensitivity to A. fumigatus

Occurs in 1% asthma patients

25% adults with cystic fibrosis

Bronchial obstruction with mucous plugs

Breathlessness

Coughing up thick sputum casts, usually brown or clear

Eosinophilia

Cardinal diagnostic test elevated serum level of total IgE (>1000IU/ml), (+) skin prick test to A. fumigatus

extract or detection of aspergillus specific IgE and

IgG(precipitating) antibodies

Central bronchiectasis characteristic

Severe asthma with fungal sensitization

Many adults do not fulfill the criteria for ABPA and yet allergic to fungi

A. fumigatus as a common allergen, numerous other fungi are implicated by skin prick testing and/ or specific IgE

radioallergosorbent testing

Allergic sinusitis

Chronic sinusitis

Nasal polypscongested nasal mucosa

Sinuses full of mucoid material

Local eosinophilia and charcot leyden crystal hallmark

Removal of mucous and polyp with glucocorticoid resolution

Ethmoidectomy persistent or recurrent symptoms

Superficial aspergillosis

Keratitis and otitis externa

Local surgical debridement

Systemic and topical antifungal therapy

Otitis externa resolves with debridement and local application of antifungal agents

Diagnosis:

Culture 10-30%(+)

Molecular diagnosis faster, more sensitive

Antigen detection detection of galactomannan release from aspergillus during growth, sensitivity reduced by antifungal prophylaxis

histopathology

Definitive confirmation of diagnosis require

a. Positive culture of a sample taken directly from an

ordinarily sterile site

b. Positive results of both histologic testing and culture of

a sample taken from affected organ

Halo signs present 7 days early in neutropenic patients and good prognosis

Outcome:

Invasive aspergillosis

curable if immune reconstitution occurs

50% mortality if treated

100% mortality if diagnosis is missed

Allergic and chronic forms not curable

Cerebral, endocarditis, bilateral extensive invasive pulmonary aspergillosis very poor outcomes

Invasive infection late stage AIDS or relapsed uncontrolled leukemia and recipients of allogeneic

hematopoietic stem cell transplants poor outcome