1. Clin Med IIInfectious Disease Lecture 1 – Fungal Diseases – Spirochetal Diseases – Mycobacterial Diseases

2. Fungal Diseases – Candidiasis – Cryptococcosis – Histoplasmosis – Pneumocystis

3. Candida albicans. Fusarium spp. (C)Aspergillusfumigatus (arrow, conidia). (D)Cryptococcus neoformans (arrows, capsule). (E)Coccidioidesspp (single arrow, arthroconidia; dotted arrow, spherule with endospores). (F)Histoplasmacapsulatum, budding intracellular yeast forms.

4. Candiasis • Common normal flora • Can become opportunistic pathogen • Numerous risk factors • If no underlying cause found, persistent candidiasis  possible HIV infection

5. Cutaneous Candiasis • Superfically denuded, beefy red lesions • Usually in skin folds with satellite papules and pustules • Often with pruritis which may be severe • Labs—budding yeast clusters and pseudohyphae under high-power microscopy after 10% KOH prep • Culture can confirm diagnosis • Read—differential diagnosis in text

6. Cutaneous Candiasis

7. Cutaneous Candiasis

8. Cutaneous Candidiasis • General Treatment – Keep area dry, expose to air, discontinue offending agent if possible • Paronychia/Nails– Clotrimazole 1% solution topically BID or thymol 4% in ethanol topically QD • Skin – Hydrocortisone 1% cream BID with either Nystatin ointment BID or clotrimazole cream 1% BID • Vulvar/Anal Mucous Membranes – • Vaginal—fluconazole 150 mg PO x 1 dose; or intravaginalclotrimazole, miconazole, terconazole, or nystatin • Recurrent/Intractable – long term suppressive therapy; may be non-albicanson culture and respond to oral itraconazole 200 mg BID for 2-4 weeks

9. Cutaneous Candidiasis • Balanitis – more common in uncircumsised men • Topical nystatin ointment for mild lesions • Soaking in dilute aluminum acetate 15 minutes BID • Chronicity or relapses—reinfection from sexual partner • Mastitis – lancinating pain and nipple dermatitis in lactating women • oral fluconazole 200 mg PO QD or topical gentian violet 0.5% • Prognosis – varies from easily cured to recurrent or intractable

10. Oral Candidiasis • Usually present with mouth and/or throat discomfort • Creamy white, curd-like patches overlying erythematous mucosa • +/- angular cheilitis

11. Oral Candidiasis • Diagnosis—clinical; may do wet prep with KOH • Treatment—listed in text—fluconazole, ketoconazole, clotrimazole, nystatin • In patients with HIV, longer courses of therapy are needed • 0.12% chlorhexidine or hydrogen peroxide—local relief • Refractory cases—oral itraconazole or voriconazole • Nystatin powder to dentures TID-QID for several weeks

12. Mucosal Candidiasis • Esophageal involvement—most frequent type of significant mucosal disease • Substernal odynophagia, gastroesophageal reflux, nausea without substernal pain • Oral candidiasis—often associated but not always present • Diagnosis—best confirmed by endoscopy with biopsy and culture • Treatment—depends on severity of disease • If able to swallow and adequate oral intake—PO fluconazole or itraconazole solution for 10-14 days • If significantly ill or fluconazole-refractory—oral or IV voriconazole, IV amphotericin B, IV capsofungin, IV anidulafungin, or IV micafungin

13. Mucosal Candidiasis • Vulvovaginal—occurs in 75% of women in their lifetime • Acute vulvar pruritis, burning vaginal discharge, dyspareunia • Diagnosis—often clinical; can confirm with KOH prep or culture • Treatment—Intravaginal topical azole preparations (see text) or single dose of fluconazole 150 mg orally • Recurrence is common—see maintenance therapy

14. Mucosal Candidiasis

15. CandidalFunguria • Usually resolves with antibiotic discontinuance or removal of bladder catheters • Asymptomatic—treatment not indicated • Symptomatic funguria—oral fluconazole 200 mg PO QD x 7-14 days • Newer generation azoles and echinocandins not recommended

16. Disseminated Candidiasis • Non-albicans species account for over 50% of blood isolates and have different resistance patterns • See text for recommended drugs for each species • Hepatosplenic Candidiasis—from aggressive chemo and prolonged neutropenia in patients with underlying hematologic cancers • Fever and abdominal pain weeks after chemotherapy • Negative blood cultures—neutrophil count often recovered • Elevated alkaline phosphatase • Fluconazole or lipid formulation of amphotericin B

17. Disseminated Candidiasis • Problematic diagnosis • Candida isolated from mucosa without invasive disease • Blood cultures positive only 50% of the time in disseminated infection • Decision to treat for Candida – based on each patient • Antifungal therapy is rapidly changing based on addition of new agents and emergence of non-albicans species • Less critically ill and no recent azole exposure—fluconazole 800 mg IV initially, then 400 mg IV daily • More severe illness or recent azole exposure—echocandin • Continue treatment for 2 weeks after last + blood culture and resolution of signs and symptoms of infection • Once patients are clinically stable, IV therapy can be changed to oral

18. Candidal Endocarditis • Rare—usually with exposure to healthcare setting • Increased frequency on prosthetic valves in the first few months after surgery • Diagnosis—culturing candida from emboli or vegetations at the time of valve replacement • Therapy—amphotericin 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 infections

19. Candidal Endocarditis

20. Candidal Endocarditis

21. Cryptococcosis • Cryptococcosisneoformans—an encapsulated budding yeast found worldwide in soil and on dried pigeon dung • Cryptococcosisgatii—related species that can also cause disease • Transmitted via inhalation • Clinically apparent cryptococcal pneumonia is rare in immunocopmetent patients • Most common cause of fungal meningitis

22. Cryptococcus

23. Cryptococcosis • Pulmonary disease: simple nodules  widespread infiltrates  respiratory failure • Three main patterns on CXR in immunocompetent pts • solitary or multiple masses of more than 5 mm in diameter • patchy, segmental or lobar air space consolidation • nodular or reticulonodular interstitial changes • Immunosuppression 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.full

24. Cryptococcosis

25. Cryptococcosis • Disseminated disease: can involve any organ, but CNS disease predominates • Headache is usually the first symptom of meningitis • Confusion, mental status changes, cranial nerve abnormalities, nausea, vomiting • +/- Nuchal rigidity and meningeal signs • C gatii – neurologic signs due to space occupying lesions • Primary C neoformans infection of skin can mimic bacterial cellulitis • Can see clinical worsening with improved immunologic status

26. Cryptococcosis

27. Cryptococcosis

28. Cryptococcosis

29. Cryptococcosis • Respiratory tract disease—diagnosed by culture of respiratory secretions or pleural fluid • Meningeal/CNS disease—lumbar puncture is preferred diagnostic procedure • Increased opening pressure, variable pleocytosis, increased protein, decreased glucose • Gram stain of CSF—budding, encapsulated fungal cells • Cryptococcal capsular antigen in CSF and culture together establish diagnosis in over 90% of cases • MRI is more sensitive than CT in finding CNS abnormalities such as cryptococcomas

30. Cryptococcosis • Initial azole therapy—not recommended for acute cryptococcal meningitis • IV amphotericin B initially x 2 weeks, followed by 8 weeks of oral fluconazole • Can add flucytosine—improved survival but increased risk for toxicity • Frequent repeated LPs or ventricular shunting if there is high CSF pressure or hydrocephalus • Switching from IV amphotericin B to oral fluconazole— • Favorable clinical response (decreased temperature, improvement in headache, N/V, and MMSE score) • Improvement in CSF biochemical parameters • Conversion of CSF culture to negative

31. Cryptococcosis • Similar regimen for non-AIDS patients with cryptococcal meningitis – continue until CSF cultures are negative and CSF antigen titers are below 1:8 • Maintenance antifungal therapy is important after acute episode in HIV cases • Fluconazole 200 mg/daily is preferred maintenance therapy • Possible to stop secondary prophyalxis with fluconazole in pts with AIDS who have had good response to antiretroviral therapy • Patients without AIDS—6-12 months of fluconazole as maintenance therapy

32. Cryptococcosis • Poor prognostic factors for cryptococcosis: • Activity of predisposing conditions • Increased age • Organ failure • Lack of spinal fluid pleocytosis • High initial antigen titer • Decreased mental status • Increased ICP • Disease outside the nervous system

33. Histoplasmosis • Histoplasmacapsulatum—dimorphic fungus isolated from soil contaminated with bird or bat droppings in endemic areas • Infection takes place by inhalation of conidia • In lungs, conidia convert to small budding cells that are engulfed by phagocytes • Proliferates and undergoes lymphohematogenous spread to other organs

34. Histoplasmosis

35. Histoplasmosis • Most cases are asymptomatic or mild and go unrecognized—incidental radiographs may show calcifications in lungs, spleen • Symptomatic—mild, influenza-like illness; 1-4 days • Moderately severe symptomatic infections—diagnosed as atypical pneumonia—fever, cough, and mild central chest pain; 5-15 days

36. Histoplasmosis

37. Acute Histoplasmosis • Frequently in epidemics • Marked prostration, fever, and comparatively few pulmonary complaints • May last from 1 week to 6 months but is rarely fatal

38. Progressive Disseminated Histoplasmosis • Often in pts with HIV or other immunosuppresion • Fever and multiple organ system involvement • CXR—miliary pattern • Can have fulminant presentation • Fever, dyspnea, cough, weight loss, prostration, oropharyngeal mucous membrane ulcerations, hepatosplenomegaly, IBD-like symptoms

39. Subacute/Chronic ProgressivePulmonary Histoplasmosis • Older patients • Various lesions on radiographs • Heals with fibrosis

40. Chronic Progressive Disseminated Histoplasmosis • Middle-aged to elderly men with no known condition causing immunosuppression • Similar presentation to acute disseminated histoplasmosis • Can be fatal if not treated

41. Complications of PulmonaryHistoplasmosis

42. Histoplasmosis—Labs • Anemia of chronic disease • Bone marrow involvement • Elevations in alkaline phosphatase, LDH, ferritin, AST • Sputum culture rarely positive except in chronic disease • Antigen testing of bronchoalveolarlavage • Antigen testing of urine and serum • Blood or bone marrow cultures • Biopsy of affected organs

43. Histoplasmosis--Treatment • Progressive localized disease and mild-moderately severe nonmeningeal disease • itraconazole 200-400 mg/d orally divided BID • Treatment of choice—overall response rate 80% • More severe illness • IV amphotericin B • AIDS-related histoplasmosis • Lifelong suppressive therapy with itraconazole • No evidence that antifungal agents improve granulomatous or fibrosingmediastinitis

44. Pneumocystosis • Pneumocystisjiroveci – worldwide distribution • Symptomatic disease is rare in general population, but most people have had asymptomatic infections by a young age • Overt infection—interstitial plasma cell pneumonia • Epidemics of primary infections — infants with comorbid conditions • Sporadic cases in older children and adults with altered immunity • Transmission unknown—most likely airborne • Pneumocystis pneumonia (PCP) occurs in up to 80% of AIDS patients without prophylaxis and is a major cause of death

45. Pneumocystosis • Extrapulmonary findings are rare • Sporadic form of disease—abrupt onset of fever, tachypnea, shortness of breath, cough • Pulmonary findings on exam may be slight and disproportionate to degree of illness and CXR findings • Adult pts may present with spontaneous pneumothorax • AIDS pts will have other evidence of HIV-related disease

46. Pneumocystosis • CXR—varying findings—most commonly show diffuse “interstitial” infiltration • No pleural effusions • ABG—can be normal; usually hypoxemia and hypocapnia • Isolated elevation or rising levels of LDH—sensitive but not specific • Serologic tests—unhelpful • elevated (1-3)-β-D-glucan has reasonably good sensitivity and specificity for diagnoses of PCP • Cannot be cultured—may be stained from sputum

47. Pneumocystosis

49. Pneumocystosis • Can start empric therapy if disease suspected clinically • Oral TMP-SMZ is preferred agent because of low cost and high bioavailability • Second-line—Clindamycin/Primaquine, Dapsone/TMP, Pentamidine, Atovaquone • Continue therapy 5-10 days before changing agents • Duration of treatment—14 days for non-AIDS patients, 21 days for AIDS patients • Supportive O2 therapy to maintain pulse oximetry >90%

50. Pneumocystosis • Primary prophylaxis should be given to HIV pts with CD4 counts <200 cells/mcL, CD4 percentage <15%, weight loss, or oral candiasis • Secondary prophlyaxis—to pts with a history of PCP until they have had a durable virologic response to antiretroviral therapy for at least 6 months and CD4 count persistently >200 cells/mcL • Prognosis—varies greatly depending on treatment • Endemic infantile form—20-50% mortality without early and adequate treatment, only 3% with early treatment • Sporadic immunodeficienty form—nearly 100% mortality without treatment, 10-20% in AIDS patients with treatment, 30-50% in other immunodeficient patients with treatment • Recurrences common in immunodeficient patients without prophylaxis