ID Subspeciality Rounds 12/9/08 Dr.Akshra Verma Dr.Janet Jokela.

ID Subspeciality ID Subspeciality RoundsRounds

12/9/0812/9/08

Dr.Akshra VermaDr.Akshra Verma

Dr.Janet JokelaDr.Janet Jokela

CaseCase 74y/o WM with lethargy and confusion x 1 74y/o WM with lethargy and confusion x 1

dayday Hemoptysis : 2-3 monthsHemoptysis : 2-3 months No fever but chills presentNo fever but chills present Lost 40lb of weight – 1yrLost 40lb of weight – 1yr ROS: Dyspepsia, malena x2, hematuria – 2 ROS: Dyspepsia, malena x2, hematuria – 2

daysdays

2 months back- noted to have a left upper 2 months back- noted to have a left upper lobe cavitary lesionlobe cavitary lesion

CaseCase PAST MEDICAL HISTORY: COPD, Spondylolisthesis, PAST MEDICAL HISTORY: COPD, Spondylolisthesis,

GERD, BPH, Hypertension, Diabetes with Nephropahty, GERD, BPH, Hypertension, Diabetes with Nephropahty, CKD stage IIICKD stage III

Allergies: Iodine (loss of consciousness)Allergies: Iodine (loss of consciousness)

Medications:  Medications:   1.    Actos1.    Actos

2.    Byetta 2.    Byetta 3.    Valsartan 3.    Valsartan 4.    Vicodin4.    Vicodin

5.    Diclofenac5.    Diclofenac  

SOCIAL HISTORY:  Smoker 1PPD since age 14, quit 3 SOCIAL HISTORY:  Smoker 1PPD since age 14, quit 3 weeks ago. No alcohol. weeks ago. No alcohol.

 6.    Prilosec 7.    Flomax 8.   .Mometasone

 9.    Niacin  10.  Lovastatin

Exam: T:97.6 °FExam: T:97.6 °F P:119 P:119 BP: 97/58 BP: 97/58 RR: 23  RR: 23  O2 sat 98 % on 6L NCO2 sat 98 % on 6L NC

Chest: Coarse breath sounds, Breath Chest: Coarse breath sounds, Breath sounds diminished b/lsounds diminished b/l

130.5324.8

7.9117

139

4.0

115

17

55

2.9113

What is your differential?What is your differential?

What tests do you want What tests do you want next?next?

Chest x-rayChest x-ray

CT scanCT scan

Lab work upLab work up

Pneumococcal and Legionella urine Pneumococcal and Legionella urine antigen- negative.  antigen- negative. 

RSV negative.  RSV negative.  Mycoplasma antibody negativeMycoplasma antibody negative LAP: 280LAP: 280

Previous work upPrevious work up   FNAC x 2  FNAC x 2 

Cytology revealed organisms consistent with Cytology revealed organisms consistent with histoplasmosishistoplasmosis

Culture was negativeCulture was negative Cultures for AFB and fungus were negative on bothCultures for AFB and fungus were negative on both

 studies. studies. No malignancyNo malignancy

  istoplasma screen was positive - M band was istoplasma screen was positive - M band was noted on histoplasma immunodiffusionnoted on histoplasma immunodiffusion

Histoplasma urine antigen negative at that timeHistoplasma urine antigen negative at that time Results not available for current admissionResults not available for current admission

Work up for Wegener’s negativeWork up for Wegener’s negative  

Pulmonary Pulmonary HistoplasmosisHistoplasmosis

Causative agent: Histoplasma capsulatumCausative agent: Histoplasma capsulatum Found worldwideFound worldwide United States- midwestern states located in the United States- midwestern states located in the

Ohio and Mississippi River valleysOhio and Mississippi River valleys Reservoir : soil contaminated with bird or bat Reservoir : soil contaminated with bird or bat

droppingsdroppings Portal of entry- lungsPortal of entry- lungs Low-inoculum exposure in a healthy individuals- Low-inoculum exposure in a healthy individuals-

asymptomatic asymptomatic Large inoculum or immunosuppressed- severe and Large inoculum or immunosuppressed- severe and

potentially fatal, acute diffuse pulmonary infection potentially fatal, acute diffuse pulmonary infection

Clinical PresentationClinical Presentation Asymptomatic pulmonary histoplasmosis Asymptomatic pulmonary histoplasmosis Symptomatic pulmonary histoplasmosis - AcuteSymptomatic pulmonary histoplasmosis - Acute

Subacute pulmonary infection weeks to months following Subacute pulmonary infection weeks to months following exposureexposure

Fever, chills, headache, myalgia, anorexia, cough, and Fever, chills, headache, myalgia, anorexia, cough, and pleuritic chest pain (2-4 weeks following exposure)pleuritic chest pain (2-4 weeks following exposure)

Coryza and sore throat are not typical - alternative Coryza and sore throat are not typical - alternative diagnosesdiagnoses

Radiographs- focal infiltrates and mediastinal or Radiographs- focal infiltrates and mediastinal or hilar lymphadenopathy hilar lymphadenopathy Diffuse reticulonodular/ miliary pulmonary infiltrates Diffuse reticulonodular/ miliary pulmonary infiltrates

Chronic pulmonary histoplasmosis Chronic pulmonary histoplasmosis  Xray- fibrotic apical infiltrates with cavitation Xray- fibrotic apical infiltrates with cavitation

Does pulmonary histoplasmosis Does pulmonary histoplasmosis always need treatment?always need treatment?

Indications for Indications for antifungal therapyantifungal therapy

AntifungalsAntifungals Lipid/Liposomal formulation of amphotericin Lipid/Liposomal formulation of amphotericin

B B 3.0–5.0 mg/kg daily IV 3.0–5.0 mg/kg daily IV

Deoxycholate formulation of amphotericin BDeoxycholate formulation of amphotericin B 0.7–1.0 mg/kg daily IV 0.7–1.0 mg/kg daily IV

ItraconazoleItraconazole 200 mg 3 times PO daily for 3 days and then 200 200 mg 3 times PO daily for 3 days and then 200

mg once or twice PO daily mg once or twice PO daily Other azoles-second line: Fluconazole, Other azoles-second line: Fluconazole,

ketoconazole, posaconazole, voriconazole ketoconazole, posaconazole, voriconazole No role of echinocandinsNo role of echinocandins

Monitoring response to Monitoring response to therapytherapy

Histoplasma antigenuria and/or Histoplasma antigenuria and/or antigenemia, levels decrease during antigenemia, levels decrease during therapy therapy

Levels increase in 90% of those who Levels increase in 90% of those who relapserelapse

Measure antigen levels Measure antigen levels before treatment is initiated, at 2 weeks, at before treatment is initiated, at 2 weeks, at

1 month, and then approximately every 3 1 month, and then approximately every 3 months during therapy and for at least 6 months during therapy and for at least 6 months after treatment is stoppedmonths after treatment is stopped

Acute Pulmonary Acute Pulmonary HistoplasmosisHistoplasmosis

Mild-to-Moderate

Moderately Severe to Severe

1. Lipid formulation of amphotericin B for 1–2 weeks followed by itraconazole

2. The deoxycholate formulation of amphotericin B

3. Methylprednisolone during the first 1–2 weeks for patients who develop respiratory complications

1.Treatment is usually unnecessary 2. Itraconazole for 6–12 weeks is recommended for patients whocontinue to have symptoms for >1 month

Chronic Cavitary Chronic Cavitary Pulmonary Pulmonary

HistoplasmosisHistoplasmosis Itraconazole for at least 1 year is Itraconazole for at least 1 year is

recommendedrecommended Montior Blood levels of itraconazole Montior Blood levels of itraconazole

at 2 weeks to ensure adequate drug at 2 weeks to ensure adequate drug exposureexposure

Complications for Complications for Pulmonary Pulmonary

HistoplasmosisHistoplasmosis PericarditisPericarditis Arthritis/ Erythema NodosumArthritis/ Erythema Nodosum Mediastinal lymphadenitisMediastinal lymphadenitis Mediastinal GranulomaMediastinal Granuloma Mediastinal FibrosisMediastinal Fibrosis BroncholithiasisBroncholithiasis Pulmonary NodulePulmonary Nodule

Disseminated Disseminated histoplasmosishistoplasmosis

Clinical illness that does not improve after Clinical illness that does not improve after at least 3 weeks at least 3 weeks of of observation and that is associated with observation and that is associated with physicalphysical or or radio-graphicradio-graphic findings and/or findings and/or laboratory evidence laboratory evidence of involvement of of involvement of extrapulmonary tissues. extrapulmonary tissues.

Hepatosplenomegaly, mucosal ulcers, skin lesions, gastrointestinal Hepatosplenomegaly, mucosal ulcers, skin lesions, gastrointestinal involvementinvolvement

Pancytopenia, progressive elevation of hepatic enzyme levels, Pancytopenia, progressive elevation of hepatic enzyme levels, increased lactate dehydrogenase level, and increased serum ferritin increased lactate dehydrogenase level, and increased serum ferritin level. level.

Laboratory evidence : demonstration of granulomas with yeasts re-Laboratory evidence : demonstration of granulomas with yeasts re-sembling H. capsulatum in extrapulmonary tissues, growth in sembling H. capsulatum in extrapulmonary tissues, growth in culture of H. capsulatum, and persistent antigenuria and/or culture of H. capsulatum, and persistent antigenuria and/or antigenemia.antigenemia.

Progressive Progressive Disseminated Disseminated

HistoplasmosisHistoplasmosisMild-to-Moderate

Moderately Severe to Severe

1. Liposomal amphotericin B (3.0 mg/kg daily) is recommended for 1–2 weeks, followed by oral itraconazole for a total of at least 12 months

2. Substitution of another lipid formulation at a dosage of 5.0 mg/kg daily

3. The deoxycholate formulation of amphotericin B (0.7–1.0 mg/kg daily) is an alternative

1. Itraconazole for at least 12 months is recommended

2. Lifelong suppressive therapy with itraconazole (200mg daily) may be required in immunosuppressed patients if immunosuppression cannot be reversed and in patients who relapse despite receipt of appropriate therapy

Role of Prophylaxis in Role of Prophylaxis in immunosuppressed immunosuppressed

patientspatients Prophylaxis with itraconazole (200 mg daily) is Prophylaxis with itraconazole (200 mg daily) is recommended in patients with recommended in patients with HIV infection with CD4 HIV infection with CD4 cell counts <150 cell counts <150 cells/mm3 in specific areas of cells/mm3 in specific areas of endemicity where the incidence of histoplasmosis is 110 endemicity where the incidence of histoplasmosis is 110 cases per 100 patient-yearscases per 100 patient-years

Prophylaxis with itraconazole (200 mg daily) may be Prophylaxis with itraconazole (200 mg daily) may be appropriate in specific circumstances in other appropriate in specific circumstances in other immunosuppressed patientsimmunosuppressed patients Active histoplasmosis during the past 2 yearsActive histoplasmosis during the past 2 years History of pulmonary infection, with radiographic findings showing History of pulmonary infection, with radiographic findings showing

infiltrates, nodules, or lymphadenopathy without a clear etiology;infiltrates, nodules, or lymphadenopathy without a clear etiology; Histoplasma antigenuria; or anti-Histoplasma complement fixation Histoplasma antigenuria; or anti-Histoplasma complement fixation

antibodytiters >=1:32.antibodytiters >=1:32.

CNS HistoplasmosisCNS Histoplasmosis

Liposomal amphotericin B Liposomal amphotericin B (5.0 mg/kg (5.0 mg/kg daily for a total of 175 mg/kg given over daily for a total of 175 mg/kg given over 4–6 weeks) followed by itraconazole 200 4–6 weeks) followed by itraconazole 200 mg 2 or 3 times daily) for at least 1 year mg 2 or 3 times daily) for at least 1 year and until resolution of CSF and until resolution of CSF abnormalities, including Histoplasma abnormalities, including Histoplasma antigen levels, is recommendedantigen levels, is recommended

Measure blood levels of itraconazoleMeasure blood levels of itraconazole

Take home pointsTake home points Itraconazole is the preferred azole for initial therapy Itraconazole is the preferred azole for initial therapy

for patients with mild-to-moderate histoplasmosis and for patients with mild-to-moderate histoplasmosis and as step-down therapy after receipt of amphotericin Bas step-down therapy after receipt of amphotericin B

Severe or moderately severe histoplasmosis -Severe or moderately severe histoplasmosis -amphotericin B formulation initiallyamphotericin B formulation initially Monitor electrolytes, renal function, blood cell countMonitor electrolytes, renal function, blood cell count

Measure Itraconazole drug levels during the first Measure Itraconazole drug levels during the first monthmonth

Hisoplasma urine or serum antigen to document Hisoplasma urine or serum antigen to document response to therapyresponse to therapy

Questions?Questions?