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Clin Med IIInfectious Disease

Lecture 1 Fungal Diseases Spirochetal Diseases Mycobacterial DiseasesFungal Diseases

Candidiasis Cryptococcosis Histoplasmosis Pneumocystis

Candida albicans. Fusarium spp. (C)Aspergillus fumigatus (arrow, conidia). (D)Cryptococcus neoformans (arrows, capsule). (E)Coccidioides spp (single arrow, arthroconidia; dotted arrow, spherule with endospores). (F)Histoplasma capsulatum, budding intracellular yeast forms.

CandiasisCommon normal floraCan become opportunistic pathogenNumerous risk factorsIf no underlying cause found, persistent candidiasis possible HIV infection

Cutaneous CandiasisSuperfically denuded, beefy red lesions Usually in skin folds with satellite papules and pustulesOften with pruritis which may be severeLabsbudding yeast clusters and pseudohyphae under high-power microscopy after 10% KOH prepCulture can confirm diagnosisReaddifferential diagnosis in text

Cutaneous Candiasis

Cutaneous Candiasis

Cutaneous CandidiasisGeneral Treatment Keep area dry, expose to air, discontinue offending agent if possibleParonychia/Nails Clotrimazole 1% solution topically BID or thymol 4% in ethanol topically QDSkin Hydrocortisone 1% cream BID with either Nystatin ointment BID or clotrimazole cream 1% BIDVulvar/Anal Mucous Membranes Vaginalfluconazole 150 mg PO x 1 dose; or intravaginal clotrimazole, miconazole, terconazole, or nystatin Recurrent/Intractable long term suppressive therapy; may be non-albicans on culture and respond to oral itraconazole 200 mg BID for 2-4 weeksCutaneous CandidiasisBalanitis more common in uncircumsised menTopical nystatin ointment for mild lesionsSoaking in dilute aluminum acetate 15 minutes BIDChronicity or relapsesreinfection from sexual partnerMastitis lancinating pain and nipple dermatitis in lactating womenoral fluconazole 200 mg PO QD or topical gentian violet 0.5% Prognosis varies from easily cured to recurrent or intractable Oral CandidiasisUsually present with mouth and/or throat discomfortCreamy white, curd-like patches overlying erythematous mucosa+/- angular cheilitis

Oral CandidiasisDiagnosisclinical; may do wet prep with KOHTreatmentlisted in textfluconazole, ketoconazole, clotrimazole, nystatinIn patients with HIV, longer courses of therapy are needed0.12% chlorhexidine or hydrogen peroxidelocal reliefRefractory casesoral itraconazole or voriconazoleNystatin powder to dentures TID-QID for several weeksMucosal CandidiasisEsophageal involvementmost frequent type of significant mucosal diseaseSubsternal odynophagia, gastroesophageal reflux, nausea without substernal painOral candidiasisoften associated but not always presentDiagnosisbest confirmed by endoscopy with biopsy and cultureTreatmentdepends on severity of diseaseIf able to swallow and adequate oral intakePO fluconazole or itraconazole solution for 10-14 daysIf significantly ill or fluconazole-refractoryoral or IV voriconazole, IV amphotericin B, IV capsofungin, IV anidulafungin, or IV micafunginMucosal CandidiasisVulvovaginaloccurs in 75% of women in their lifetimeAcute vulvar pruritis, burning vaginal discharge, dyspareuniaDiagnosisoften clinical; can confirm with KOH prep or cultureTreatmentIntravaginal topical azole preparations (see text) or single dose of fluconazole 150 mg orallyRecurrence is commonsee maintenance therapyMucosal Candidiasis

Candidal FunguriaUsually resolves with antibiotic discontinuance or removal of bladder cathetersAsymptomatictreatment not indicatedSymptomatic funguriaoral fluconazole 200 mg PO QD x 7-14 daysNewer generation azoles and echinocandins not recommendedDisseminated CandidiasisNon-albicans species account for over 50% of blood isolates and have different resistance patternsSee text for recommended drugs for each speciesHepatosplenic Candidiasisfrom aggressive chemo and prolonged neutropenia in patients with underlying hematologic cancersFever and abdominal pain weeks after chemotherapyNegative blood culturesneutrophil count often recoveredElevated alkaline phosphataseFluconazole or lipid formulation of amphotericin B

Disseminated CandidiasisProblematic diagnosis Candida isolated from mucosa without invasive disease Blood cultures positive only 50% of the time in disseminated infectionDecision to treat for Candida based on each patientAntifungal therapy is rapidly changing based on addition of new agents and emergence of non-albicans speciesLess critically ill and no recent azole exposurefluconazole 800 mg IV initially, then 400 mg IV dailyMore severe illness or recent azole exposureechocandin Continue treatment for 2 weeks after last + blood culture and resolution of signs and symptoms of infectionOnce patients are clinically stable, IV therapy can be changed to oral

Candidal EndocarditisRareusually with exposure to healthcare settingIncreased frequency on prosthetic valves in the first few months after surgeryDiagnosisculturing candida from emboli or vegetations at the time of valve replacementTherapyamphotericin usually considered optimal along with aggressive surgical intervention

High risk patients undergoing induction chemotherapy, bone marrow transplantation, or liver transplant, prophylaxis with antifungal agents can help prevent invasive fungal infectionsCandidal Endocarditis

Candidal Endocarditis

CryptococcosisCryptococcosis neoformansan encapsulated budding yeast found worldwide in soil and on dried pigeon dungCryptococcosis gatiirelated species that can also cause diseaseTransmitted via inhalationClinically apparent cryptococcal pneumonia is rare in immunocopmetent patientsMost common cause of fungal meningitis

Cryptococcus

CryptococcosisPulmonary disease: simple nodules widespread infiltrates respiratory failureThree main patterns on CXR in immunocompetent ptssolitary or multiple masses of more than 5mm in diameterpatchy, segmental or lobar air space consolidationnodular or reticulonodular interstitial changesImmunosuppression affects pattern of pulmonary involvement--in AIDS patients interstitial changes are common and often also have lymphadenopathy.http://thorax.bmj.com/content/53/7/554.fullCryptococcosis

CryptococcosisDisseminated disease: can involve any organ, but CNS disease predominatesHeadache is usually the first symptom of meningitisConfusion, mental status changes, cranial nerve abnormalities, nausea, vomiting+/- Nuchal rigidity and meningeal signsC gatii neurologic signs due to space occupying lesionsPrimary C neoformans infection of skin can mimic bacterial cellulitisCan see clinical worsening with improved immunologic statusCryptococcosis

Cryptococcosis

Cryptococcosis

CryptococcosisRespiratory tract diseasediagnosed by culture of respiratory secretions or pleural fluidMeningeal/CNS diseaselumbar puncture is preferred diagnostic procedureIncreased opening pressure, variable pleocytosis, increased protein, decreased glucoseGram stain of CSFbudding, encapsulated fungal cellsCryptococcal capsular antigen in CSF and culture together establish diagnosis in over 90% of casesMRI is more sensitive than CT in finding CNS abnormalities such as cryptococcomasCryptococcosisInitial azole therapynot recommended for acute cryptococcal meningitisIV amphotericin B initially x 2 weeks, followed by 8 weeks of oral fluconazoleCan add flucytosineimproved survival but increased risk for toxicityFrequent repeated LPs or ventricular shunting if there is high CSF pressure or hydrocephalusSwitching from IV amphotericin B to oral fluconazoleFavorable clinical response (decreased temperature, improvement in headache, N/V, and MMSE score)Improvement in CSF biochemical parametersConversion of CSF culture to negativeCryptococcosisSimilar regimen for non-AIDS patients with cryptococcal meningitis continue until CSF cultures are negative and CSF antigen titers are below 1:8Maintenance antifungal therapy is important after acute episode in HIV casesFluconazole 200 mg/daily is preferred maintenance therapyPossible to stop secondary prophyalxis with fluconazole in pts with AIDS who have had good response to antiretroviral therapyPatients without AIDS6-12 months of fluconazole as maintenance therapy

CryptococcosisPoor prognostic factors for cryptococcosis:Activity of predisposing conditionsIncreased ageOrgan failureLack of spinal fluid pleocytosisHigh initial antigen titerDecreased mental statusIncreased ICPDisease outside the nervous system

HistoplasmosisHistoplasma capsulatumdimorphic fungus isolated from soil contaminated with bird or bat droppings in endemic areasInfection takes place by inhalation of conidiaIn lungs, conidia convert to small budding cells that are engulfed by phagocytesProliferates and undergoes lymphohematogenous spread to other organs

Histoplasmosis

HistoplasmosisMost cases are asymptomatic or mild and go unrecognizedincidental radiographs may show calcifications in lungs, spleenSymptomaticmild, influenza-like illness; 1-4 daysModerately severe symptomatic infectionsdiagnosed as atypical pneumoniafever, cough, and mild central chest pain; 5-15 days

Histoplasmosis

Acute HistoplasmosisFrequently in epidemicsMarked prostration, fever, and comparatively few pulmonary complaintsMay last from 1 week to 6 months but is rarely fatal

Progressive Disseminated HistoplasmosisOften in pts with HIV or other immunosuppresionFever and multiple organ system involvementCXRmiliary patternCan have fulminant presentationFever, dyspnea, cough, weight loss, prostration, oropharyngeal mucous membrane ulcerations, hepatosplenomegaly, IBD-like symptoms

Subacute/Chronic ProgressivePulmonary HistoplasmosisOlder patientsVarious lesions on radiographsHeals with fibrosis

Chronic Progressive Disseminated HistoplasmosisMiddle-aged to elderly men with no known condition causing immunosuppressionSimilar presentation to acute disseminated histoplasmosisCan be fatal if not treated

Complications of PulmonaryHistoplasmosis

HistoplasmosisLabs Anemia of chronic diseaseBone marrow involvementElevations in alkaline phosphatase, LDH, ferritin, ASTSputum culture rarely positive except in chronic diseaseAntigen testing of bronchoalveolar lavageAntigen testing of urine and serumBlood or bone marrow culturesBiopsy of affected organsHistoplasmosis--TreatmentProgressive localized disease and mild-moderately severe nonmeningeal diseaseitraconazole 200-400 mg/d orally divided BIDTreatment of choiceoverall response rate 80%More severe illnessIV amphotericin BAIDS-related histoplasmosisLifelong suppressive therapy with itraconazoleNo evidence that antifungal agents improve granulomatous or fibrosing mediastinitisPneumocystosisPneumocystis jiroveci worldwide distributionSymptomatic disease is rare in general population, but most people have had asymptomatic infections by a young ageOvert infectioninterstitial plasma cell pneumoniaEpidemics of primary infections infants with comorbid conditionsSporadic cases in older children and adults with altered immunityTransmission unknownmost likely airbornePneumocystis pneumonia (PCP) occurs in up to 80% of AIDS patients without prophylaxis and is a major cause of death

PneumocystosisExtrapulmonary findings are rareSporadic form of diseaseabrupt onset of fever, tachypnea, shortness of breath, coughPulmonary findings on exam may be slight and disproportionate to degree of illness and CXR findingsAdult pts may present with spontaneous pneumothoraxAIDS pts will have other evidence of HIV-related diseasePneumocystosisCXRvarying findingsmost commonly show diffuse interstitial infiltrationNo pleural effusionsABGcan be normal; usually hypoxemia and hypocapniaIsolated elevation or rising levels of LDHsensitive but not specificSerologic testsunhelpfulelevated (1-3)--D-glucan has reasonably good sensitivity and specificity for diagnoses of PCPCannot be culturedmay be stained from sputumPneumocystosis

PneumocystosisCan start empric therapy if disease suspected clinicallyOral TMP-SMZ is preferred agent because of low cost and high bioavailabilitySecond-lineClindamycin/Primaquine, Dapsone/TMP, Pentamidine, AtovaquoneContinue therapy 5-10 days before changing agentsDuration of treatment14 days for non-AIDS patients, 21 days for AIDS patientsSupportive O2 therapy to maintain pulse oximetry >90%

PneumocystosisPrimary prophylaxis should be given to HIV pts with CD4 counts 20 mm/hr (50%)Mildly abnormal LFTs (30%)Mild anemia or microscopic hematuria 10% or lessSerologic teststwo-test approach recommendedELISA test - confirm with Western immunoblot assay for IgM/IgGSuspected early diseaseacute and convalescent titersLyme DiseasePrevention No human vaccine availablePreventive measuresProphylactic antibiotic guidelinesin textTreatmentTable 34-4

Lyme DiseaseMost patients respond to appropriate therapy with prompt resolution of symptoms within 4 weeksLong term outcome generally favorableJoint pain, memory impairment, decreased function due to pain are common subjective complaintsReferinfectious disease specialist if atypical or prolonged AdmitIV antibiotics symptomatic CNS or cardiac diseaseSecond-degree AV block or third-degree AV blockFirst-degree AV block with PR interval 300 milliseconds or moreRocky Mountain Spotted FeverMost cases occur outside Rocky Mountain area56%--North Carolina, South Carolina, Tennessee, Oklahoma, ArkansasEndemic in Central and South AmericaCausative pathogen Rickettsia rickettsii Gram negative aerobic bacteriumTransmitted by tick biteIncreasing incidense in USRocky Mountain Spotted FeverMost serious rickettsial diseaseSevere multiorgan dysfunction and Symptoms appear 2-14 days after bite Characteristic rashdays 2-6 of feverInitially on wrists and anklesSpreads to arms, legs, and trunk for 2-3 daysInvolves palms and soles Facial flushing, conjunctival injection, hard palate lesions10% of casesno or minimal rash

Rocky Mountain Spotted FeverLabsthrombocytopenia, hyponatremia, elevated AST/ALT, hyperbilirubinemiaCSFhypoglycorrhachia, mild pleiocytosisSevere casesDICDiagnosisimmunohistologic (including PCR) studies of skin biopsiesMust do as soon as skin lesions are apparent and before antibiotics are startedSerologic tests confirm diagnosis not valid in early disease

Rocky Mountain Spotted FeverTreatmentdoxycycline (chloramphenicol if pregnant)Fever usually ends 48-72 hrsContinue medication for at least 3 d after afebrileMortality rate 3-5% on average as high as 70% in untreated elderlyMyocarditis is leading cause of deathProtective clothing, tick-repellent chemicalsNo prophylactic therapy

Mycobacterial Diseases

Tuberculosis Atypical Mycobacterial DiseaseTuberculosisOne of the worlds most widespread and deadly illnesses20-43% of the worlds population15 million patients in USDisproportionately high among malnourished, homeless, and residents of overcrowded and substandard housingMore common in HIV positive patients

TuberculosisInfection by inhaling airborne droplet nuclei with viable Mycobacterium tuberculosis organismsTubercule bacilli are ingested by alveolar macrophagesInfection if the pathogen escapes macrophage microbicidal activityIf infection occurs, there is usually lymphatic and hematogenous dissemination before an adequate immune response is mountedTuberculosisPrimary tuberculosisdissemination of M tuberculosis with usually no clinical signsProgressive primary tuberculosisin 5% of patients; inadequate immune response to contain initial infection Latent tuberculosiscannot transmit organism but are susceptible to reactivation of disease if immune system becomes impairedResistance is becoming more prevalent15% of US cases are resistant to one or more antituberculous drugsMDRTB outbreaks have been associated with 70-90% mortality rates and 4-16 week survival ratesPulmonary TuberculosisSlowly progressive symptoms of malaise, anorexia, weight loss, fever, and night sweatsChronic cough is most common pulmonary symptomAppear chronically ill and malnourishedChest examination may be normal or may show classic findings such as posttussive apical rales

Pulmonary TuberculosisDefinitive diagnosisrecovery of pathogen from cultures or identification by DNA/RNA amplification techniquesCultures may require 12 weeks to grow Fiberoptic bronchoscopy, bronchial washings and transbronchial biopsies can help diagnosis in patients with suspicious symptoms but negative sputum smearsNeedle biopsies of pleuragranulomatous inflammation in approximately 65% of patientsPulmonary TuberculosisCXRsmall homogenous infiltrates, hilar and paratracheal lymphadenopathy, segmental atelectasisPleural effusion may be sole abnormalityCavitationif progressive primaryGhon and Ranke complexes in some patientsReactivation TBusually in apical or posterior segments of upper lobes, but other sites in up to 30%Miliary pattern in disseminationHIV patientsearly findings resemble non-HIV patients; later disease tends toward atypical findings

For Your ReadingTuberculin Skin TestingBe familiar with table 9-15!Have a good idea of what is a positive test and what isnt for common patient populationsTreatmentKnow basic principles of treatmentReview table 9-16 look at names of drugs, general monitoring tests you would order for a patient on anti-TB therapy, and which drugs (if any) have significant side effects/interactionsWhat would be a good maintenance regimen for latent TB?

Atypical Mycobacterial Diseases10% of mycobacterial infectionsAmong the most common opportunistic infections in HIV patients

Atypical MycobacteriaPulmonary -- MAC causes a chronic, slowly progressive pulmonary infection resembling TB in immunocompetent pts; M kansasii can also produce clinical disease resembling TB but which progresses more slowly Lymphadenitis in adults usually due to TB; in children, most are due to nontuberculous mycobacteria Skin/Soft Tissueabscesses, septic arthritis, osteomyelitisDisseminatedMAC can range from asymptomatic colonization to a spectrum of diseasesTreatmentrifabutin, azithromycin, clarithromycin, ethambutolcombination of 2 or more agentsProphylaxisfor all HIV patients with CD4 counts 50 or less

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