BY Craig Rundbaken, D.O. Respiratory and Valley Fever Clinic Staff member Banner Del E. Webb Memorial Hospital and Banner Boswell Memorial Hospital Raise awareness by educating you on signs, symptoms, diagnosis and treatment of valley fever Discuss pitfalls in diagnosis and treatment including utility of serology and azole drug side effects Discuss the new cocci skin test Spherusol ALWAYS consider cocci in differential diagnosis of respiratory illness/cap in the endemic zones***** 1
No conflict of interest to disclose 2
Dimorphic fungus in the desert soil Saprophyte-Parasitic Soil surface to 6 inches below Medical name: Coccidioidomycosis Class; Ascomycetes Species: Immitis and Posadasii Size: 3-5 microns; 14 trillion per square inch 1 spore required for infection Most common is Cocci for Coccidioidomycosis Desert fever San Joaquin Valley fever Desert rheumatism Older term: Wernicke Posadasii disease 3
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RUPTURED SPHERULE Not contagious person-to-person; infection occurs by inhaling arthrospore No animal-to-person transmission Lab workers face hazard Animals at risk: dogs, cattle, sheep; rarely cats Sea animals at risk: dolphins, otters Zoo animals at risk: llamas, kangaroos, monkeys Rare to transmit by direct contact with cocci abscess 6
ADHS case definition adapted from CDC and Prevention case definition Culture, histopathology, or molecular evidence of presence of cocci OR Laboratory confirmed case requires one of following ; serologic(serum, csf, body fluid) by EIA, Latex agglutination, or tube precipitin OR Detection of cocci igg by immunodiffusion, EIA or complement fixation Cocci skin test conversion from a negative to a positive after the onset of clinical s/s 7
1994 578 2003 2,695 1995 623 2004 3,667 1996 655 2006 5,535 **1997 958 2007 4,832 1998 1,474 2008 4,768 1999 1,812 2009 10,233 2000 1,917 2010 11,883 2001 2,301 2011 16,467 2002 3,118 2012 12,920 2013 7113 JAN-Dec 2014-5624 JAN- Dec 2015-7660 Jan-Feb 2016-1098 8
Fatigue!!! Cough Shortness of breath Fever Night sweats Pleuritic chest pain Headache Weight loss Muscle aches and joint pain (desert rheumatism) Hemoptysis from pneumonia or cavity Erythema nodosum Erythema multiform Toxic erythema Weight loss/anorexia Arthritis Conjunctivitis 9
Delayed hypersensitive rxn to variety antigens. Inflamed subcutaneous fat cells Most common pretibial but other extensor surfaces arms, thighs regress 1-2 weeks heal 1-2 mo. Good prognostic sign; not specific to cocci treatment; corticosteroids, colchicine, potassium iodide, nsaids 10
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Immune complex deposition(igm) in microvasculature/hypersensitive rxn Red, target-shaped crops of skin lesions Can be itchy and necklace distribution Common upper body, inner thighs May have blister, vesicular or be hive like Cause drugs, lymphoma, cocci, infections treatment 12
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Fine, red diffuse rash Associated with fever Dissipates in about 1 week 14
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Male Elderly On corticosteroid/immunosuppressive medication Organ transplant recipient Infants Women who are pregnant Lymphoma/immunocompromised (HIV/AIDS) Race: African Americans, Filipinos 18
Tube precipitin (TP) antibodies Complement fixing (CF) antibodies Immunodiffusion(IDTP,IDCF) Enzyme linked immunoassays(eia) Latex tests A positive serologic test for coccidioidal antibodies is highly presumptive of cocci infection. A negative test should never exclude a cocci infection. Repeat serologic tests will increase the sensitivity for diagnosis 19
Most common: EIA and immunodiffusion Complement fixation antibodies False positive and false negative occur thus cannot definitively include or exclude vf dx without supporting clinical data.*********** Titers correlate with severity, treatment response Eosinophils may be elevated Sedimentation rate and C-reactive protein IgM: becomes measurable earlier in acute phase usually between the first (50%) and third (90%) weeks of onset. IgG or CF Ab: becomes measurable between the second and 28th week post onset. May remain for several months but is usually related to disease activity. Antibodies drop to negative on serology testing when illness resolved. IgG also Note: Serologic studies are less sensitive then often thought, especially in self-limited clinical cases Positive serologies are helpful, but negative ones cannot be relied on to rule out disease. 20
Laboratory Diagnosis (especially in CAP) Other benefits of Dx may include: Avoidance of use of antibiotics Earlier identification of complications Decreased need for added expensive studies Reduction in patient anxiety Chang, et al. Emerg Infect Dis 2008;14 Tissue biopsy Polymerase chain reaction Sputum analysis Urine analysis Pleural or cerebral spinal fluid analysis 21
3% endemic population is infected per year Symptoms occur in 40% of patients Up to 60% of patients may be asymptomatic Small percent disseminate/chronic 22
Developed and standardized by C.E. Smith and associates 1930 s Supplies depleted and development stopped 1980 s. Distribution of human cases 23
Greater than 150,000-200,000 cases per year Cases increase due to population growth, tourism, travel Upsurges seen after dust storms, cycles of drought and rain, earthquakes Recovery generally confers permanent immunity No person-to-person spread Dry, alkaline soil Hot summers: 70F to over 100F Low altitudes Scant rainfall: 5-20 inches per year Mild winters: 40F to 54F 24
Hiking, biking Baseball Conor Jackson, 2009 All terrain vehicles Archeology Dirt biking Golf PGA Gary Kraft, 2001 Construction workers Landscapers Working around desert sand Telephone line workers Military personal Solar industry 25
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The Original Spherulin skin test was produced and marketed by Berkley Biologicals. Later sold and purchased by Allermed now Nielsen Bioscience reformulated and studied. Phenolic preservative 27
The reformulation is 0.4% phenol as preservative, and residual thimerosal concentration was reduced to1;1,000,000. 1.27 ug spherule-derived coccidioidin in a volume of 0.1ml is spherusol. 4 studies performed before FDA approval Confirmed 98%sensitive and 98% specific Spherusol is a skin test antigen indicated for the detection of delayed type hypersensitivity to Coccidioides immitis in individuals with history of pulmonary coccidioidomycosis. Approved for ages 18-64 y/o. 28
Documented conversion from negative to positive can be used to help diagnose primary pulmonary cocci. A positive skin test is protective against a second infection A host with previous ST positive, a new pneumonia is not likely to be cocci Development of a positive ST in a patient with known pulmonary cocci is a good prognostic sign. Failure to develop a positive skin test in a patient with known cocci is a bad prognostic sign and is associated with a higher frequency of relapse when therapy discontinued. 29
A single 0.1ml intradermal injection. 0.1ml intradermal injection to the volar surface of the forearm using a tuberculin syringe(0.5-1.0ml) and a ½ inch 26-27 gage needle. 5-10 mm diameter bleb formed from this Induration at injection site to be evaluated at 48 hours after administration. At 48 hours plus or minus 4 hours measure response. A mean induration of >5 mm is considered a positive delated response to spherusol 30
A robust cellular immune response indicates that cocci infection has occurred and that the host has developed lifelong immunity Rarely systemic reaction can occur Larger then expected skin reactions can rarely occur usually dime to quarter size Immunosuppressive medication or immune deficiencies can cause false negative tests. 31
Infiltrates Cavity Pleural effusions Residual nodule Hilar and mediastinal adenopathy 32
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History and physical exam Clinical symptoms are supportive Laboratory and imaging findings Clinical consideration Assess for extra-pulmonary disease (dissemination) in 0.5-1% cases Nearly all medications discussed will be FDA off label The only FDA approved medications with cocci indication Ketoconazole Amphotercin B deoxycholate 39
Begins with a history and exam Determine the severity, location, and chronicity of infection Define the presence of extrapulmonary cocci skin, soft tissue, bone, meningitis Azoles Ketoconazole(nizoral) Itraconazole(sporonox) Fluconazole(Diflucan) Voriconazole(v-fend) Posaconazole Amphotericin preparations amphotericin deoxycholate/lipid associated amphotericins Newer agents Nikkomycin z attacks chitin in cell wall Under study-not available 40
Tolerable Studies confirm both itraconazole and fluconazale efficacious Long term use acceptable and can use for extrapulmonary disease. Monitor liver enzymes and for medication drug interactions. I.e. warfarin, statins Class; Triazole; Good oral bioavailability 400-800 mg a day Most common agent used for cocci infections Well tolerated Infrequent hepatitis but monitor liver function/drug interactions Fungal static by inhibiting key enzyme components of fungal cell wall Mitigate common side effects such as dry skin, dry lips, constipation, and alopecia 41
Water Soluble Well absorbed from GI tract Good CSF penetration 80% Excreted in urine Halve dose for creatinine clearance <50% Class; Triazole Dose usual 200 mg bid up to 800 mg a day Requires gastric acid for absorption Requires measurements of serum levels Well tolerated Has shown superiority to fluconazole for skeletal involvement Monitor LFT s and can cause arrhythmias, HF Absorption increased with cola beverages or cranberry juice 42
N/V (dose dependent, divide doses) AST/ALT elevation Rash Hypokalemia (esp >400mg/d) htn/ edema Has Black Box label warning heart failure caused by a direct negative inotropic effect Therapeutic role in cocci not clarified Has been used in salvage cases unresponsive to other treatment or co-infections with aspergillosis Typically 200-400 mg q day PO/IV Inhibits fungal sterol synthesis Melanoma and squamous cell skin cancer has been seen with Voriconazole. Photosensitivity reactions 43
Visual changes Blurred vision, photopsias, photophobia, color changes Transient, reversible, tend to dissipate with repeated dosing Hepatotoxicity elev. AST/ALT Photosensitivity Need for sunscreen (Literature reports of melanoma, sq cell) Class; Triazole Dosage usual 400 mg bid Requires fatty meal for absorption Blocks synthesis of components of cell wall membrane Typically used for cases resistant to other medication Possibly fungalcidal, role not clarified 73% succcess in those failing other standard regimens. 44
HA GI N/V, diarrhea Hepatotoxicity elevated LFT s Hypokalemia Rash Q-Tc prolongation Class; Imidazole Inexpensive/ FDA approved 400 mg a day 200 mg bid Interferes with testosterone production and cortisol responses. Uses when other medication not available Damages cell membrane by altering permeability Pharmaceutical safety profile favors triazoles 45
Currently under study Inhibitor of chitin synthase, a major component of fungal cell wall Hopefull studies show fungalcidal First medication to show efficacy against cocci IV or intrathecal not oral IV not effective for cocci meningitis Often used for rapid progressive infections Amphotercin B deoxycholate 0.5-1.5 mg/kg iv daily or every other day Infusion toxicity ; Fever,rigors, hypotension, also electrolyte imbalance(mg,phos,k), renal failure 46
Safer alternative 3 formulations available *ABCD; Ampho B cholestyrl sulfate complex (Amphotec) *ABCL; Ampho B lipid complex(albecet) * Liposomal Ampho B (AmBisome) Less frequent febrile rxn Expensive 2-5 mg/kg IV daily No data demonstrated improved efficacy for Cocci No good in vivo studies showing effectiveness against cocci Limited case reports showing mixed results One study shows some effectiveness when combined with AmB Not recommended for use currently 47
Large abscess Enlarging cavities/lesions despite medical treatment Fistulas Destructive lesions Joints Hemorrhage Unstable spine Presence of bony sequestration Fluconazole 400 mg a day, most common Treat or not based on severity and risk group Follow up in clinic monthly with labs and chest radiograph evaluation Most important to utilize clinical symptoms as guide to length of treatment As symptoms, x-rays, labs improve, discontinue therapy and follow patient in 1-2 months Advise patient call if any flare up of symptoms 48
Less than 1% Meninges, bone, joints, skin GI and GU tracts Spleen, liver, adrenal gland, pericardium, Spreads via circulation Joint lesion-unifocal, ankles and knees Cyclosporine, tacrolimus, sirolimus Ca channel blockers Benzodiazepines (most) Warfarin Statins (many) Steroids 49
Carbamazepine Phenobarbitol Phenytoin Rifampin Rifambutin Difficult in endemic areas Plant grass, pave roads, avoid dust storms, dust control at construction sites, consider mask, close truck/car windows,water construction sites-minimize dust At present no practical methods exist from eliminating from the soil Be extra careful if you are in high risk group; consider N-95 mask Educate landscapers about blowers 50
A negative lab test does not rule out valley fever Valley fever can present like any other respiratory illness and appears similar to cancer on medical imaging Immune status and co-morbid medical conditions contribute as major factor in rapid deterioration We need better diagnostic tests, medication and a vaccine for valley fever 51
When a valley fever patient has another problem or simultaneous problems (lung cancer, metastatic cancer, lymphoma, infection) Medication interacts with warfarin, statins, etc. Monitor liver function laboratory, typically monthly with clinic visit Rash mistaken allergic reaction missing valley fever diagnosis A negative blood test does not rule out valley fever False positives lab also occur Utilize clinical skills to diagnose not solely lab test Valley fever center for excellence(www.vfce.arizona.edu/) Arizona Department of Health Services (www.azdhs.gov/) Craig Rundbaken D.O. (Airmedvfc.com) Arizona victims of valley fever www.arizonavictimsofvalleyfever.org Valley fever alliance of Arizona clinicians VFAAC Mayo clinic www.mayoclinic.org 52
Infectious Disease Society of America (IDSA) Guidelines Revised 2005 November http://www.uphs.upenn.edu/bugdrug/antibi otic_manual/coxyrx.pdf 53