Cutaneous mycosis I.

Superficial (attacks only stratum corneum, and no host response, and therefore no inflammation): tinea versicolor (hyper or hypopigmented patchesaround neck like a turtleneck)in the yeast form everyone has it normally, but the hyphae form cauases the tinea versicolor: main culprit: yeast Malassezia furfur and treated with selsenium sulfide (was entire body), topical azoles (ketoconazole) and in refractory cases systemics (terbinafine and itraconazole, just like onychomychosis--WHY????); common in humid, hot places some people get it, some dont, bc some people are more susceptible Cutaneous (infections of the dermis and epidermis with inflammation unlike superficial, but fungi do not invade viable tissue): mucocutaneous candidiasis and DERMATOPHYTOSIS: a. Microsporum genus cause tiniea capitis, corporis, and pedis, but NOT tinea unguium; most common world wide. Most common species: M. canis b. Epidermapyhton fluccosum is the only medically important species of the genus and causes tinea cruris and tinea pedis c. Tricophyton spp: MOST COMMON IN THE USmost common species is T. tonsuranscan cause infections in all locations: Dermatophytosis use keratin as their primary source and are characterized by location of the infection: tinea pedis, tinea corporis, tinea capitis, tinea barbae, tinea cruris (groin), tinea manuum (hand), tinea unguium (nails); tinea comes from the raised erythema of tinea corporis,. Cellular immunity is a key factor in control of them so immunocompromised and HIV patients will have more dermatophytosis. Dermatophytoses can also be characterized according to their environmental reservoir: 1) Anthropophilic: in humans (T. Tonsurans), 2) zoophilic: in animals (microsporum canis), and 3) geophilic: in soil (Microsporum gypseum) Tinea corporis: ringworm which forms an erythematous, round, raised patch; it can be treated only with topicals such as clotrimazole and miconozole; there is also topical terbinafine, but it costs more so not preferred Tinea capitis: occurs in two ways: 1) ectothrix invasion: arthroconidia form on outside of hair shaft, but cuticle is destroyedbecause it is outside the hair bulb, the hair can grow back; 2) endothrix invasion: arthroconidia form within hair shaft, leaving cuticle intactbc it is inside the hair, the bulb is permanently damaged. Breakage of hairs leads to black dot alopecia, and a kerion forms as a result of increased T cell immune response which causes even more inflammation and damage to the hair bulbs and can even cause cervical lymphadenopathy Tinea capitis mainly happens in children, infants, usually urban people like African Americans or Hispanics, and transmitted from child to child or from animals (if see alopecia, ask about petsalso presents with erythema, papules, scaling, exudate); main species responsible is Tricophytan tonsurans in the US (causes endothrix invasion and is more subtle) and it does not fluoresce with Woods lamp; most common tinea capitis in the world is caused by Microsporum canis (causes the ectothrix invastioncuts straight through hair); TREATMENT of children with tinea capitis: systemic with fluconazole

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(griseofulvin old school but fluc is better) and terbinafine and topical with ketoconazole shampoo and selenium sulfide shampoo (Selsen). Do hail pull and culture them, but KOH is not as good Tinea pedis is most common dermatophytosis. May be common portal for cellulitis injury, esp in diabetics. Tricophyton rubrum is most common cause of tinea pedis; THREE CLINICAL FORMS: interdigial, moccasin (sole of foot and side), and vesiculobullous; sometime hand can be involved with feet (touching feet causes autoinoculation); onychomycosis also can come with tinea pedis; interdigital is easily treated with topicals such as miconazole and clotrimazole. In the case of onychomycosis, then: ONYCHOMYCOSIS: source of infection for Staph and strepproblematic for people with vascular disease. The fungus is eating away at the nail bed, and has gotten inside, so needs to be treated with systemics: itraconazole and terbinafine. Caused by T. rubrum and T. mentagophytes. Three clinical subtypes: proximal subungual, distal subungual (DSO), and white superficial (WSO); DSO are most commonhyphae enter distally under nail plate and spread proximally, digesting stratum corneum of nail bed as well as nail plate. PSO most common by T. rubrum, almost exclusively presented by immunocompromisedearly indication of HIV. WSO caused by T. mentagrophytes minimal inflammation, since dorsal surface of nail is attacked, and no viable tissue is involvedmore common in water sports Tinea cruris (groin) is invasion of the hair follicles that can easily be confused with cutaneous candida infection. Concomitant tinea pedis or onychomycosis can predispose to recurrence suggesting possible transfer of organisms. Sporotrichosis: gardening, and spreads along nerves, and gets pricked and cant feel ON BOARDS sometimes

-If the fungus are resistant, the fungi in the environment need to be destroyed, so get all the clothes and hair pieces and boil them in the laundry -MOST mycoses are not transmissible but two are: 1) dermatophytosis and 2) vulvovaginal candidiasis (general Candida?) -LAB DIAGNOSIS: KOH or calcofluor prep of scale scraped from edge of lesion; KOH test distinguishes between detmatophytes and Candida albicans versus psoriasis. Tinea capitis diagnosed on KOH exam of hair if causesd by Tricophytan spp as spores can attach to or reside on the hair shaft; culture it on Sabouraud dextrose agar with cycloheximide for four weeks; any growth of dermatophytes is significant, since most dermatophytes are zoophilic or anthropophilic and cannot be contaminants. Tinea capitis baused by Microsporum. Audounii or M. canis fluoresces blue-green under Woods light examination

Opportunistic Mycoses I. Altered T cell function (AIDS, chemotherapy, radiation therapy patients) a. Mucocutaneous candidiasis: (comes from HIV, pregnangy, age, antibiotics): give topicals (clotrimazole or nystatin), or oral fluconazole but for esophageal where orals cannot be given, give IV fluconazole, or IV echinocandins i. oropharyngeal candidiasis (thrush)laryngeal strideor (loud breathing)

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ii. esophageal candidiasis: dysphagia presents, weight loss bc of no eating; only in esophagus with squamous non-keratinized esophagus, and not in gastric mucosa, since Candida does not do well theregive fluconazole iii. cutaneous candidiasis: most common in diaper dermatitis of babieskeep dry, seen only early postpartum; also under breasts, under armpitsfor fat people skin surfaces rubbing against each other will be moistred and inflamedbut it has to have satellites (if only red, then just dermatitis and give steroids); common in diabetics. Topicals and orals depending iv. keratitis: v. chronic mucocutaneous candidiasis: inherited disorder of cell immunity to Candida with concomitant polyendocrinpothies (disease where autoimmunity is against several different endocrine organsin this case kidney, thyroid, adrenals, etc.) Autosomal recessive. Give fluconazole b. Cryptococcus: yeast that is CAPSULATED; causes meningoencephalitis; main species: Cryptococcus neoformans. Causes pulmonary disease in some patients as well (atopic patients), but mainly CNS with meningoencephalitis. Only T lymphopenia not neutropenia causes it: HIV patients, and immunosuppressed transplant recipients are at increased risk. CD4 less than 100/microliter. It is also inhaled just like Aspergillus and Zgomycoses (???????), and replicates in the lung and hematogenously disseminates and actually gets across the BBB, which is why it causes meningoencephalitis. Do LP for CNS diseasethese are humongous bc of the capsule, and the capsule is toxic too, so tough to eradicate. It is heteropolysaccharide capsule which produces a lot of antigen (so easily diagnosed by LP) and inhibits phagocytosis, but the antigen is not chemotactic. KO mutants are less virulent. Cryptococcus neoformans also produce phenoloxidase which produces melanin which inhibits oxygen-dependent killing mechanisms. It is visualized with the FONTANA-MASSON stain. Treated by Ampo + 5FC, a lot of relapse, so add some oral fluconazole a few months later, to prevent it. Fluconazole is a tiny molecule, so it gets across the BBB. Also check intracranial pressure when diagnosing it, bc it can cause elevated pressure and it will get into the calcarian fissure and cause blindness (so blindness can be caused by Candida endopthamitis and cryptoccus neoformans). If too much pressure, call neurosurgeon to drain it. c. Pneumocytosis: Pneumocystis carinii/jiroveci is most common species. Opportunistic and causes pneumonia, not much else. T cell decrease by HIV, immunosuppression, and corticosteroids for lupus or something else can increase risk for it. There is infiltrate in alveolus, so there is shunt with perfusion, but not ventilation, and they are tachypnic andhypoxic, but not chest pain, because it is not ANGIOINVASIVEonly Aspergillus and zygomycoses. Also, Aspergillus does not cause hypoxia to that degree, since it causes dead space. Treatment: TRIMEOPRIM-SULFAMETHOXAZOLE shuts down folate synthesis. Altered phagocytic activity (neutropenia) a. Invasive candidiasis (all Candida covered here except mucocutaneous): people at risk are those with surgery, corticosteroids, neutropenia, bone marrow transplantation that destroys barriers. Albicans most virulaent and common; it is always present but other commensals prevent it from taking over, and antibiotics will allow it space. DEEPLY INVASIVE includes candidemia, endocarditis, actue disseminated candidiasis, renal candidiasis (anything Staph can do, Candida can do it); for this, there needs to be major destruction-needs help since it cannot get in directly itselfneutropenia, transplantation, surgery, antibiotics. GIVE IV fluconazole, or echinocandins, add AmB as backup for Albicans. For non-albicans, give echinocandins right away bc it might be resistant. i. Invasive candidiasis is so virulent because it has powerful adherence and colonization and can penetrate through mucosal barriers, and is angioinvasive, so

it has hematognous dissemination; it can get into the eyes, so you need to do a dilated retinal exam, so if patient cannot see well, it might be invasive Candidasis (Candida Endopthalmitis if it gets into the eye). It generally adheres to the choriocappilaris (capillary lamina of choroid); they might have broken into the vitreous and grow, and there is then an inflammatory response in the eye, which is not good; at this point you aspirate out the vitreous and inject AmB in the eye. If not done, it will destroy the eye, esp the macula. Systemic infections due to invasive Candida can result in inflammation, but if the person is neutropenic, then the hyphae will grow unhindered. The host response can be seen on an H&E stain, but it is not sensitive for fungal detetion. PAS stains the acid polysaccharide cell wall of the fungi, and Gamorris Methanamine silver (GMS) deposits silver on the cell wal of the fungus, increasing sensitivity of detection. ii. In particular, Candida albicans is virulent: it has surface receptorsepithelial and endothelial cells, and the cell wall can serve to preven immunodetection; it also has hydrolytic enzyme activityacid protease and phospholipases; it has host mimicry, since it produces a surface complement C3d receptor; it is dimorphic (converts from yeast to hyphal form in hostreverse of classical dimorphism); germ tube is used for ID; it also activates metalloenzymes (which our own damaged tissue secretes to destroy tissue, but this time it is not damaged tissue, but the fungus is secreting it to destroy perfectly good tissue). SYSTEMIC CANDIDIASIS causes disseminated disease and SEPSIS b. Aspergillosis: filamentous fungi known as moldsunlike Candida, it is not normally part of our flora as Candida is. It IS ALWAYS OPPORTUNISTICchronic granulomatous disease or bone versus host disease from bone marrow transplant for instance. Always ask why a person has it, bc there is some immune problem. Normally, in culture, it looks like a tree with a round bush with the conidia flying off from the top, but in our bodies, they become ANGULAR DICHOTOMOUSLY BRANCHING SEPTATE HYPHAE. Main species fumigatus, which has many of the same virulence factors as Candida Albicanssuch as adherence receptors, hydrolytic enzymes, complement inhibitor, and toxins. Treatment: first line therapy is voriconazole, and liposomal AmB (V on vorizonazole like branching septate hyphae). i. Produces aflatoxins which cause hepatocellular carcinoma from peanuts and grains in warm temp, and can cause endemic cancer ii. Can cause allergies in atopic individuals (tendency to develop allergies) iii. Respiratory problems in people who have TB or sarcoidosisAspergilloma in lungs that cause bleeding and hemoptysis. It ONLY HAPPENS with 1) neutropenic, or 2) corticosteroid patients. Neutropenia is usually a result of leukemia therapy, corticosteroids for transplant patients, autoimmune disease. Can also happen with CGD (chronic granulomatous disease). What happens: you inhale the conidia (sporescolloquial); normally, the alverolar macrophages and defensins/cathepsins will destroy them (through non-oxidative killing), but in the case of a compromised host, there is no killing either because of lack of phagocytosis ore lack of fusion of lysosome and phagosome, and there is germination where the conidia form hyphae and get into the pleural space and eventually blood vessels causing ischemia, thrombosis, and infarction, and potentially hematogenous dissemination (pleuritis causes pain when inhaling). ASPERGILLUS WILL ALWAYS HAVE DICHOTOMOUSLY BRANCHING septate hyphae that is Y shaped. They usually invade blood vessels with necrosis of tissue. Can cause death by infarction of different organs. HALO SIGN: nodule with dense infarction with light part that is fluid from ischemic alveola that is

leakingcalssic for angioinvasive organismssuch as Aspergillus. When the patitent covers from the neutropenia, there is a crescent sign with the neutrophils coming in, showing intact tissue, and invading, with wedge shape ischemic potion still present. iv. Infections: keratitis following corneal trauma c. Zygomycosis (Mucormycosis): opportunistic fungi that are ubiquitous; Rhizopus species most common. Diabetics are at high risk for rhinocerebral zygomycosis with infection in the peri-orbital, ethmoidal sinus area because the zygomyces can eat all the high glucose, and also patients with pulmonary problems who are neutropenic, for the same reasons as Aspergillus. Just like Aspergillus, they are angioinvasive organisms, that cause infarction. They invade the orbit and eye, and sometimes brain, and can even cause cranial nerve palsies. They can directly invade or thrombose the vessels surrounding the eye or the optic nerve. Much larger than Aspergillus though, (15 vs 5 microns), and they are NONSEPTATE HYPHAE at right angles, not V shaped like Aspergillus. They grow so fast, that you need a lid on the culture, and they will push the lid off. They have sporangiosphores which beares a large sac-like structures called sporangia, and that is filled with sporangiospores which break off like conidia of dermatophytes. HALO image is for all angioinvasive organisms including zygo. Causes coagulative necrosis of tissue. TREATMENT ONLY AmB (A for Zbeginning to end), also adjunctive therapy by surgery, and get back innate host defense by stopping the corticosteroids, for example. So three-pronged approach: AmB, with surgery and immune system revitalization. If disagnose this, start AmB right away, but call ENT surgeon right away CANDIDA is OPPORTUNISTIC: should not be seen; it is NORMALLY present in the skin, GI tract, GU tract, oral mucosa; if white plaques are seen with pseudohypae, hyphae, and budding yeast cells it is Candida; presents in infants often, since their immune systems are not as advanced; GIVE Nyastatin to children with it DO NOT USE ITRACONAZOLE for Candida, and do NOT USE FLUCONAZOLE for Aspergillus; do NOT use Voriconazole for Zygo but otherwise Voriconazole is broad spectrum like AmB (yeasts and molds) Angioinvasive organisms: Aspergillus and zygomycoses, and Candida Candida can get into eye, but also Cryptococcus neoformans Conidia inhaled for Aspergillus and Blastomyces dermatidis; arthroconydia of Cocci inhaled. Sporangiospores for zygo; microconidia for Histo. Aspergillus spores 5 microns. Zygo 15 microns; Blastomyces 15 microns. Cocci spherules 80 microns Ergosterol is also in protozoa such as Leishmania, so AmB can also function against them Clotrimazole/miconazole are topicals for 1) diaper rash, 2) oroesophageal candidiasis, and 3) vulvo-vaginal candidiasis Posaconazole is more potent than intra and has a lower MIC All azoles are heptatotoxic; all of them, except for fluconazole are anti-yeast and mold, but fluconazole is only anti-yeast, so it does not work against Aspergillus; all azoles are eliminated by the liver, except for fluconazole which goes out by kidney. (AmB goes out by both liver and kidney) Cultures of fungus are insensitive, and people can go completely undiagnosed, and even die, so a better way is to use either 1-3 B-D-glucan (for Candida and Aspergillus) and galactomannan (for Aspergillus) as a biomarker, and these are part of the cell wall of the fungus and are released in the bloodstream. These two can also be targeted for cell degradation by echinocandins Echinocandins are circular to resist proteolytic degradationattacks ONLY Candida and Aspergillus

All routes of elimination are hepatic, and the only ones that are eliminated by the kidney are AmB (liver also), fluconazole (mainly kidney, some liver), and 5FC. Nystatin for oropharyngeal candidiasis, vulvo-vaginal candidiasis, diaper rash Spores of histo are small in us (2-3 microns) and at 25 C they become humongous macroconidia with hyphae

Pathogenic Infection These fungi cause infections in normal, non-immunocompromised hosts; portal of entry: inhalation of asexual spores from environment; they HAVE SYMPTOMS LIKE TB, but they are not transmitted, bc they are DIMORPHIC, and in tissue, they are yeasts, and it is in the hyphae form that they reproduce. So when the person has contracted it, they cannot transmit it, bc in them it is in the yeast form. Diseases are asymptomatic or mild in most hosts, but atopic people have DISSEMINATED, PROGRESSIVE INFECTION, but more common in T-cell compromised hosts, or corticosteroids, TNF alpha inhibitors, etcso happens in normal people, but still increased risk of immune-compromised patientsand that T cell leukopenic, not neutropenic. Pathology is usually chronic inflammation and granuloma formation. VERY TOXIC, and can kill people, so if suspected, write it down, so people in micro can put it under hood. TREATMENT for all of them: itraconazole for stable patients; treat for six months, bc it is intracellular so hard to kill; if person is going into septic shock bc of Histo, unstable, give lipo formulation AmB, which get into cell

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Histoplasma capsulatum a. Present in Maryland but mainly in soil and caves enriched with bird or bat fecal material (Ohio Mississippi River valley regionspretty much all of east US, except for coastline of Atlantic); fecal matter of birds, especially Starlings, with hyperosmotic is used by histoplasma since it is too toxic for most bacteria. MICROCONIDIUM are the infective inoculum b. TNF alpha inhibitors such as infliximab, entanercept, adalimumab cause TB infection and Histothese are both granulomatous diseases, so a histological slide will show caseating granulomas; distinguish by GMS and PAS test for fungi and acid test for bacteria. In the early part of the infection, there will be small budding yeast cells in the cytoplasm of macrophages/monocytes (intracellular); then you will see granulomas just like TB granulomas. Immunosuppressed hosts (such as HIV patients) dont have the ability to make good granulomas (like the leprematous leprosy). The neutrophils will not take part of the inflammatory response. The intracellular histo will not be hyphenated but only as yeast, because Histo is dimorphic and at 37 turns into yeast. These characteristic features will not be apparent in a culture right away, so DNA probes are used for ID, otherwise wait two weeks c. Only intracellular, not extracellular; it stays inside to evade killing by phagocytic cells; it replicates in the phagolysosome by neutralizing acid environment d. Pulmonary portal of entry; most hosts following low inoculum exposure will be asymptomatic or with mild respiratory symptoms; 5% will have mild to severe respiratory disease (atopic and also inoculum size dependent); VERY FEW will have the worstDISSEMINATED infections, which occurs in normal hosts, but more in T-cell compromised. e. Causes a disease of the reticuloendothelial system (RES)liver, spleen, lymph nodes, bone marrow, with all these other types of macrophages (Kuppfer cells, osteoclasts, etc.) so the circulating monocytes that connect these various compartments will have intracellular Histo.

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f. Very similar to Penicillium marneffei which is indigenous to Southeast Asia Coccidiones immitis a. Present in desert soil in southwest USA (south Califronia, New Mexico, west Texas, Arizona)they live in dry areas where the arthroconydia start to fly everywhere where people can inhale them. If it rains, they form hyphae and feed on surrounding organic material; once it becomes dry, they disseminate once again until it rains and they start to fly everywhere where people can inhale them. If it rains, they form hyphae and feed on surrounding organic material; once it becomes dry, they disseminate once again until it rains again; colloquially causes Valley Fever b. Presents as erythema nodosum which is a red bump on skin due to fat cell accumulation or macrophage accumulation under skin. c. Atopic people can develop more subtle disease; symptoms are vague and not specific, and diagnosis is not done by symptoms, which can be confused for lung cancer. d. Exposure by inhalation that disseminates; starts as pulmonary problem, with perhaps a bony problem (like Blasto); forms arthroconidia at room temp which is the hyphal form, and then becomes spherules in tissue. Virulent, since only one arthroconidia can kill a mouse. Spherules are humongous 60-80 microns, and are not yeast, and they release a lot of endospores which can go on and infect the rest of the body; the endospores can be destroyed by the immune system (the spherules are hard to destroy since they are so large) e. Africans and Filipinos are at higher risk Blastomyces dermatidis a. In Virginia but mainly in water in North Central (Wisconsin, Michigan, Minnesota, Illinois) and south east USA (Alabama, Mississippi) b. We inhale conidia on the terminal portion of hyphae and it transforms into large 12-15 micron (dwarf Histo) yeasts in us; neutrophils attack and then onslaught of macrophages; it does not involve RES as does Histo, but hits lung, skin, bone, urinary-tract. Presents as bony manifestation. Can simulate lung cancer or other diseases. Paracoccioides brasiliensis a. Present in South America (Columbia, Brazil) b. Estrogen protects women from infection, so mainly in males c. If itraconazole is not present, give trimethoprim sulfamethoxazole (just like pneumocystis infections)

Big three for respiratory infections: Strep. Pneumonia, H. influenza,