Clin Med II Infectious Disease Lecture 1 – Fungal Diseases – Spirochetal Diseases – Mycobacterial Diseases

Fungal 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.

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

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

Cutaneous Candiasis

Cutaneous Candiasis

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 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 weeks

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

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

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

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

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

Mucosal Candidiasis

Candidal Funguria 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

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

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

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

Candidal Endocarditis

Candidal Endocarditis

Cryptococcosis Cryptococcosis neoformans— an encapsulated budding yeast found worldwide in soil and on dried pigeon dung Cryptococcosis gatii—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

Cryptococcus

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

Cryptococcosis

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

Cryptococcosis

Cryptococcosis

Cryptococcosis

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

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

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

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

Histoplasmosis Histoplasma capsulatum— 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

Histoplasmosis

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

Histoplasmosis

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

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

Subacute/Chronic Progressive Pulmonary Histoplasmosis Older patients Various lesions on radiographs Heals with fibrosis

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

Complications of Pulmonary Histoplasmosis

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 bronchoalveolar lavage Antigen testing of urine and serum Blood or bone marrow cultures Biopsy of affected organs

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 fibrosing mediastinitis

Pneumocystosis Pneumocystis jiroveci – 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

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

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

Pneumocystosis

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%

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

Spirochetal Diseases – Lyme Disease – Syphilis – Rocky Mountain Spotted Fever

Syphilis Complex disease caused by Treponema pallidum Transmission most frequently during sexual contact Major clinical stages— early (infectious) and late, separated by a symptom-free latent phase

Primary Syphilis Stage of Invasion Typical lesion is changre at sites of inoculation Initial small erosion 10- 90 days after inoculation; develops into painless superficial ulcer with clean base and firm, indurated margins Regional lymph node enlargement Heals without treatment; may scar

Primary Syphilis Darkfield microscopy and immunofluorescent staining can help visualize pathogen Read—Nontreponemal antigen tests vs. Treponemal antibody tests

Primary Syphilis Penicillin remains preferred treatment; Doxycycline, Rocephin or Tetracycline can be used for secondary treatment Table—34-3 Jarisch Herxheimer Reaction—fever and aggravation of symptoms in hours following treatment Resolves spontaneously in 24 hours Patients with infectious syphilis must abstain from sexual activity for 7-10 days after treatment Patients sexually exposed in the last 3 months should be treated even if seronegative; if over 90 days, base treatment on serologic testing

Primary Syphilis Monitor treated pts clinically and serologically Q 3-6 mo Screen for HIV at time of diagnosis Failure of nontreponemal titers to decrease 4x by 6 mo – high risk for treatment failure Failure of titers to decrease 4x by 6-12 mo – repeat HIV screening, consider lumbar puncture, retreat Persistent signs and symptoms or 4x or greater increase in in nontreponemal titers – failed therapy or reinfection

Screening for Syphilis Avoidance of sexual contact—only 100% reliable method Latex or polyurethane condoms Men who have sex with men—screening every 6-12 mo High-risk individuals—every 3-6 months Pregnant women—1st prenatal visit Repeat in 3rd trimester if high risk Patients who have other STDs Patients who have known or suspected contact with patients who have syphilis

Secondary Syphilis Appears from a few weeks to 6 months after development of chancre Dissemination of Treponema pallidum  systemic signs and/or infectious lesions distant from inoculation site

Secondary Syphilis Rash—nonpruritic, macular, papular, pustular, follicular, or combinations of any of these types Generalized; involve palms and soles in 80% May see annular lesions or mucous membrane patches Condyloma lata Meningeal, hepatic, renal, bone, and joint invasion Alopecia and uveitis

Secondary Syphilis Serologic tests positive in almost all cases Moist cutaneous and mucous membrane lesions show pathogen on darkfield examination Transient CSF pleocytosis in 30-70% Immune complex hepatitis or nephritis Treatment—Same as primary syphilis unless CNS or ocular disease present, in which case treatment for neurosyphilis given

Latent Syphilis Clinically quiescent phase after disappearance of secondary lesions Early latent syphilis—first year after primary infection May relapse to secondary syphilis if undiagnosed or inadequately treated 90% of relapses occur within first year after infection Relapse is almost always accompanied by rising titer Late latent syphilis—noninfectious; over 1 year No clinical manifestations; only significant labs are positive serologic tests Can last from months to a lifetime

Latent Syphilis Early latent syphilis treatment—same as primary syphilis unless CNS disease present Late latent syphilis treatment—Table 34-3 If CNS involvement, perform LP and start neurosyphilis treatment of positive Repeat nontreponemal serologic tests at 6, 12, 24 mo HIV screen, LP, and retreat if: titers increase 4x initially high titers fail to decrease 4x by 12-24 mo signs and symptoms consistent with syphilis develop

Tertiary Syphilis May occur at any time after secondary syphilis Late lesions – possible delayed hypersensitivity reaction Localized gummatous reaction Diffuse inflammation (usually of CNS and large arteries Gummas may involve any area or organ of the body Most common types of involvement—skin, mucous membranes, skeletal system, eyes, respiratory system, GI system, cardiovascular system, nervous system

Tertiary Syphilis Skin—two types of lesions multiple nodular lesions that eventually ulcerate solitary gummas that start as painless subcutaneous nodules and then enlarge, attach to skin and ulcerate Mucous membranes—nodular gummas or leukoplakia Skeleton—destructive—periostitis, osteitis, arthritis Eyes—gummatous irits, chorioretinitis, optic atrophy, cranial nerve palsies Respiratory system—gummatous infiltrates into larynx, trachea, and pulmonary parenchyma

Tertiary Syphilis Gastrointestinal—benign, asymptomatic hepar lobatum may have cirrhotic syndrome Gastric involvement—diffuse infiltration or focal lesions Cardiovascular—10-15% of late syphilis lesions; usually starts as arteritis in supracardiac aorta and progresses to: Narrowing of coronary ostia Scarring of aortic valves Weakness of wall of aorta Neurological—multiple possible manifestations Asymptomatic meningovascular syphilis tabes dorsalis general paresis

For your reading… Neurosyphilis Syphilis in HIV patients Syphilis in pregnancy Congenital syphilis When to Refer/Admit

Lyme Disease Most common tick-borne disease in US and Europe Vectors and animal reservoirs vary with area Ticks must generally feed for 24-36 hours or more to transmit infections Most cases are in spring and summer months

Lyme Disease—Early Localized Erythema migrans 1 week after bite (3-30 d) Expands over several days May have more homogenous appearance or central intensification 10-20% of pts have atypical lesions or do not notice lesion Viral-like illness Myalgias, arthralgias, headache, fatigue +/- fever Resolves in 3-4 weeks

Lyme Disease—Early Disseminated Up to 50-60% of pts with erythema migrans—bacteremic Secondary skin lesions in 50% of patients Appear in days-weeks and resemble primary lesion Malaise, fatigue, fever, headache, cervicalgia, body aches Pathogen may sequester itself and cause focal symptoms Cardiac (4-10%) Neurologic (10-15%)

Lyme Disease—Late Persistent Months to years after initial infection Musculoskeletal, neurologic, and skin disease Classic – monarticular or oligarticular arthritis May be quite swollen but usually less painful than bacterial septic arthritis Self-limited but can have multiple recurrences Nervous system involvement is usually rare subacute encephalopathy (in US) or more severe encephalomyelitis (in Europe) Peripheral—intermittent paresthesias or radiculopathy Cutaneous—acrodermatitis chronicum atrophicans Bluish-red discoloration of distal extremity with swelling

Lyme Disease—Diagnosis Person with exposure to tick habitat with either Erythema migrans diagnosed by physician At least one late manifestation and laboratory confirmation Nonspecific abnormalities—especially early Elevated sed rate > 20 mm/hr (50%) Mildly abnormal LFTs (30%) Mild anemia or microscopic hematuria – 10% or less Serologic tests—two-test approach recommended ELISA test - confirm with Western immunoblot assay for IgM/IgG Suspected early disease—acute and convalescent titers

Lyme Disease—Prevention No human vaccine available Preventive measures Prophylactic antibiotic guidelines—in text Treatment—Table 34-4

Lyme Disease Most patients respond to appropriate therapy with prompt resolution of symptoms within 4 weeks Long term outcome generally favorable Joint pain, memory impairment, decreased function due to pain are common subjective complaints Refer—infectious disease specialist if atypical or prolonged Admit—IV antibiotics symptomatic CNS or cardiac disease Second-degree AV block or third-degree AV block First-degree AV block with PR interval 300 milliseconds or more

Rocky Mountain Spotted Fever Most cases occur outside Rocky Mountain area 56%--North Carolina, South Carolina, Tennessee, Oklahoma, Arkansas Endemic in Central and South America Causative pathogen – Rickettsia rickettsii Gram negative aerobic bacterium Transmitted by tick bite Increasing incidense in US

Rocky Mountain Spotted Fever Most serious rickettsial disease Severe multiorgan dysfunction and Symptoms appear 2-14 days after bite Characteristic rash—days 2-6 of fever Initially on wrists and ankles Spreads to arms, legs, and trunk for 2-3 days Involves palms and soles Facial flushing, conjunctival injection, hard palate lesions 10% of cases—no or minimal rash

Rocky Mountain Spotted Fever Labs—thrombocytopenia, hyponatremia, elevated AST/ALT, hyperbilirubinemia CSF—hypoglycorrhachia, mild pleiocytosis Severe cases—DIC Diagnosis—immunohistologic (including PCR) studies of skin biopsies Must do as soon as skin lesions are apparent and before antibiotics are started Serologic tests confirm diagnosis – not valid in early disease

Rocky Mountain Spotted Fever Treatment—doxycycline (chloramphenicol if pregnant) Fever usually ends 48-72 hrs Continue medication for at least 3 d after afebrile Mortality rate 3-5% on average as high as 70% in untreated elderly Myocarditis is leading cause of death Protective clothing, tick-repellent chemicals No prophylactic therapy

Mycobacterial Diseases – Tuberculosis – Atypical Mycobacterial Disease

Tuberculosis One of the world’s most widespread and deadly illnesses 20-43% of the world’s population 15 million patients in US Disproportionately high among malnourished, homeless, and residents of overcrowded and substandard housing More common in HIV positive patients

Tuberculosis Infection by inhaling airborne droplet nuclei with viable Mycobacterium tuberculosis organisms Tubercule bacilli are ingested by alveolar macrophages Infection if the pathogen escapes macrophage microbicidal activity If infection occurs, there is usually lymphatic and hematogenous dissemination before an adequate immune response is mounted

Tuberculosis Primary tuberculosis—dissemination of M tuberculosis with usually no clinical signs Progressive primary tuberculosis—in 5% of patients; inadequate immune response to contain initial infection Latent tuberculosis—cannot transmit organism but are susceptible to reactivation of disease if immune system becomes impaired Resistance is becoming more prevalent—15% of US cases are resistant to one or more antituberculous drugs MDRTB outbreaks have been associated with 70-90% mortality rates and 4-16 week survival rates

Pulmonary Tuberculosis Slowly progressive symptoms of malaise, anorexia, weight loss, fever, and night sweats Chronic cough is most common pulmonary symptom Appear chronically ill and malnourished Chest examination may be normal or may show classic findings such as posttussive apical rales

Pulmonary Tuberculosis Definitive diagnosis—recovery of pathogen from cultures or identification by DNA/RNA amplification techniques Cultures may require 12 weeks to grow Fiberoptic bronchoscopy, bronchial washings and transbronchial biopsies can help diagnosis in patients with suspicious symptoms but negative sputum smears Needle biopsies of pleura—granulomatous inflammation in approximately 65% of patients

Pulmonary Tuberculosis CXR—small homogenous infiltrates, hilar and paratracheal lymphadenopathy, segmental atelectasis Pleural effusion may be sole abnormality Cavitation—if progressive primary Ghon and Ranke complexes in some patients Reactivation TB—usually in apical or posterior segments of upper lobes, but other sites in up to 30% Miliary pattern in dissemination HIV patients—early findings resemble non-HIV patients; later disease tends toward atypical findings

For Your Reading… Tuberculin Skin Testing Treatment Be familiar with table 9-15! Have a good idea of what is a positive test and what isn’t for common patient populations Treatment Know basic principles of treatment Review 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/interactions What would be a good maintenance regimen for latent TB?

Atypical Mycobacterial Diseases 10% of mycobacterial infections Among the most common opportunistic infections in HIV patients

Atypical Mycobacteria Pulmonary -- 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 Tissue—abscesses, septic arthritis, osteomyelitis Disseminated—MAC can range from asymptomatic colonization to a spectrum of diseases Treatment—rifabutin, azithromycin, clarithromycin, ethambutol—combination of 2 or more agents Prophylaxis—for all HIV patients with CD4 counts 50 or less

Questions?