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108 FUNGAL INFECTIONS

108 FUNGAL INFECTIONS
Harrison’s Manual of Medicine

108

FUNGAL INFECTIONS

Cryptococcosis
Candidiasis
Aspergillosis
Histoplasmosis
Blastomycosis
Coccidioidomycosis
Paracoccidioidomycosis
Mucormycosis
Miscellaneous Mycoses

Fusariosis

Malassezia Infection

Pseudallescheriasis

Sporotrichosis
Bibliography

Fungi can appear microscopically as either yeasts or molds. Most pathogenic fungi are saprophytic in nature; they cause infection when airborne spores reach the lung or paranasal sinus or when hyphae or spores are accidentally inoculated into the skin or cornea. Acquisition of infection from another person is rare.
CRYPTOCOCCOSIS
EPIDEMIOLOGY/PATHOGENESIS   The yeastlike fungus Cryptococcus neoformans elaborates a large polysaccharide capsule. Humans become infected by inhalation of the fungus. Pulmonary infection is frequently asymptomatic. Dissemination, including that to the CNS, occurs via the bloodstream. Pts with late-stage HIV infection are at substantial risk for this infection, as are pts who have undergone solid organ transplantation, those with sarcoidosis, and those receiving glucocorticoid therapy.
CLINICAL MANIFESTATIONS   Meningoencephalitis   Headache, nausea, staggering gait, dementia, irritability, confusion, and blurred vision are common early symptoms. One-third of pts have papilledema at diagnosis. Fever and nuchal rigidity are often mild or lacking. Cranial nerve palsies, typically asymmetric, occur in about one-fourth of cases. With progression of the infection, deepening coma and signs of brainstem compression appear.
Pulmonary Infection   Chest pain occurs in 40% of cases and cough in 20%. CXRs commonly show one or more dense infiltrates, which are often well circumscribed.
Disseminated Infection   Some 10% of pts with cryptococcosis have skin lesions, and the vast majority of those who do also have disseminated infection. Cutaneous findings begin with one or more papular lesions, which tend eventually to ulcerate. Rare manifestations of disseminated disease include prostatitis, osteomyelitis, endophthalmitis, hepatitis, pericarditis, endocarditis, and renal abscess.
DIAGNOSIS   LP is the single most useful diagnostic test for cryptococcal meningitis. The India ink smear is positive in >50% of cases. Among non- AIDS pts, hypoglycorrhachia is present half of the time, and elevated CSF protein levels and lymphocytic pleocytosis are also common. Among AIDS pts, CSF abnormalities are less pronounced but the India ink smear is more often positive. A CSF or serum latex agglutination test is positive in 90% of cases of cryptococcal meningitis. Fungemia develops in 10–30% and is particularly common among persons with AIDS. For the diagnosis of pulmonary or disseminated cryptococcosis, biopsy (with culture) is usually required. Sputum culture is positive in only 10% of cases of cryptococcal pneumonia and serum latex agglutination in only one-third.

TREATMENT
For pts with AIDS and cryptococcosis, therapy begins with IV amphotericin B (0.7 mg/kg qd), which is administered for at least 2 weeks and until the clinical condition is stable. Thereafter, these pts receive oral fluconazole (400 mg/d). The addition of flucytosine to the amphotericin B regimen for 2 weeks has minimal impact on morbidity and mortality; its addition to fluconazole only increases GI intolerance. After infection is controlled, suppressive therapy with oral fluconazole (200 mg/d) is continued indefinitely. It is not yet known whether pts with a sustained rise in CD4+ T lymphocyte counts can safely discontinue fluconazole maintenance therapy. Surgical excision of a solitary lesion, without systemic therapy, may be appropriate for selected immunocompetent pts with no cryptococci in blood, CSF, or urine. In non- AIDS pts, the goal of therapy is to cure the infection, not merely to control its symptoms. A single intensive course is given until cultures from all previously positive sites are negative. Amphotericin B is administered either alone (0.6–0.7 mg/kg IV qd for ³10 weeks) or with flucytosine (25–37.5 mg/kg q6h). Flucytosine accelerates culture response, but grave toxicity can result unless serum levels are kept below 100 µg/mL. Use of liposomal formulations of amphotericin B for treatment of cryptococcal meningitis in pts without HIV infection is controversial.

CANDIDIASIS
ETIOLOGY/PATHOGENESIS   Candida spp., common commensals of humans, are found most often in the mouth, stool, and vagina. Candidiasis is often preceded by expansion of the commensal population as a result of broad- spectrum antibiotic therapy. Additional host factors, both local and systemic, favor infection. Examples include diabetes mellitus, HIV infection, and denture wear, all of which favor the development of oropharyngeal thrush; macerated skin (regardless of etiology), which favors the development of cutaneous candidiasis; and the third trimester of pregnancy, during which vulvovaginal candidiasis is especially common. Candida can pass from colonized surfaces to deep tissues when the integrity of the mucosa or skin is violated (as a consequence, for example, of GI perforation by trauma or surgery, use of an indwelling catheter, or mucosal damage from cytotoxic chemotherapy). Hosts who are particularly susceptible to Candida once it has traversed the integumentary barrier include neonates of very low birth weight, people with neutropenia, and pts who are using or have recently used high-dose glucocorticoids. Hematogenous seeding is particularly evident in the retinas, kidneys, spleen, and liver.
CLINICAL MANIFESTATIONS   Oral thrush presents as discrete and confluent adherent white plaques in the mouth and on the tongue. Cutaneous candidiasis presents as redness and maceration in intertriginous areas. Vulvovaginal thrush causes pruritus and discharge and is sometimes responsible for dyspareunia or dysuria. Oral and vaginal thrush, circumscribed hyperkeratotic skin lesions, dystrophic nails, and partial alopecia characterize chronic mucocutaneous candidiasis. A variety of defects in T cell function have been described in pts with this condition, who may also exhibit hypofunction of the parathyroid, adrenal, or thyroid gland. Dysphagia or substernal chest pain occurs in esophageal candidiasis, the most common type of GI candidiasis. Endoscopic findings include areas of redness and edema, focal white patches, and/or ulcers. Hematogenous dissemination presents with varied severity, ranging from fever alone to septic shock. Other findings may include retinal lesions, multiple small hepatosplenic abscesses, nodular pulmonary infiltrates, endocarditis, chronic meningitis or arthritis, and (in rare cases) focal manifestations such as osteomyelitis, pustular skin lesions, myositis, and brain abscess.
DIAGNOSIS   Demonstration of pseudohyphae on wet smear with confirmation by culture is the procedure of choice for diagnosing superficial candidiasis. Deeper lesions due to Candida may be diagnosed by histologic section of biopsy specimens or by culture of blood, CSF, joint fluid, or surgical specimens. Serologic tests for antibody or antigen are not useful.

TREATMENT
For cutaneous candidiasis, nystatin powder or a cream containing ciclopirox or an azole is applied topically. For vulvovaginal candidiasis, vaginal azole formulations are therapeutically superior to nystatin suppositories. A single oral dose of fluconazole (150 mg) is a convenient alternative but is more likely to cause adverse effects. Oral or esophageal candidiasis responds better to clotrimazole troches taken five times a day than to nystatin suspension swished and swallowed. Oral fluconazole (100–200 mg/d) is more convenient and effective in esophagitis than clotrimazole troches. Esophagitis not responding to fluconazole may warrant repeat endoscopy to exclude other conditions. Itraconazole suspension (100–200 mg/d) alleviates Candida esophagitis in some pts when fluconazole treatment fails. Pts with AIDS and recurrent oropharyngeal or esophageal candidiasis may develop azole resistance. For AIDS pts with azole-resistant disease, amphotericin B (0.3–0.5 mg/kg IV qd) may be used. Bladder thrush responds to bladder irrigation with amphotericin B (50 mg/L for 5 d); oral fluconazole may be substituted in the treatment of noncatheterized pts with candiduria. For disseminated disease, amphotericin B (0.5–0.7 mg/kg qd) is the treatment of choice. In immunocompetent pts with catheter-acquired C. albicans fungemia, the catheter should be removed in conjunction with the administration of fluconazole (400 mg/d) or amphotericin B (0.5 mg/kg qd). Therapy for candidemia should be continued for 2 weeks after the pt becomes afebrile. The Candida species involved should be considered in choosing between fluconazole and amphotericin B. For example, C. krusei is resistant to fluconazole in vitro, C. glabrata is intermediately sensitive to fluconazole, and strains of C. lusitaniae are resistant to amphotericin B. Oral fluconazole (400 mg/d) is used prophylactically against invasive candidiasis in recipients of allogeneic bone marrow transplants.

ASPERGILLOSIS
EPIDEMIOLOGY/PATHOGENESIS   Aspergillus is a mold with septate hyphae ~2–4 µm in diameter. Aspergillus species are ubiquitous in the environment and cause several syndromes, including allergic bronchopulmonary aspergillosis, aspergilloma, and invasive aspergillosis. Invasive disease originates in the lung after inhalation of Aspergillus spores and is confined almost entirely to immunosuppressed hosts. In roughly 90% of such cases, two of the following risk factors are present: neutropenia (granulocyte count <500/ µL), history of high-dose glucocorticoid therapy, or history of treatment with cytotoxic drugs. Invasive infection, which may also complicate AIDS, is characterized by hyphal invasion of blood vessels, thrombosis, necrosis, and hemorrhagic infarction.
CLINICAL MANIFESTATIONS   Allergic bronchial aspergillosis presents in pts with preexisting asthma as eosinophilia, fleeting pulmonary infiltrates, and demonstrable IgE antibody to Aspergillus. Endobronchial saprophytic pulmonary aspergillosis presents as chronic productive cough, often with hemoptysis, in pts with prior chronic lung disease, such as tuberculosis, sarcoidosis, or bronchiectasis. The term aspergilloma refers to a ball of hyphae that forms within a preexisting pulmonary cyst or cavity, usually in an upper lobe. Invasive aspergillosis in the immunocompromised host presents as an acute, rapidly progressive, densely consolidated pulmonary infiltrate. In the pt recovering from neutropenia, cavitation is a classic occurrence. Infection may spread hematogenously or by direct extension.
DIAGNOSIS   The repeated isolation of Aspergillus from sputum implies colonization or infection. The diagnosis of invasive aspergillosis is suggested by even a single isolation of Aspergillus from the sputum of a neutropenic pt with pneumonia. A biopsy and culture are usually required for definitive diagnosis, the latter for confirmation and speciation. Blood cultures are rarely positive. A fungus ball in the lung is usually detectable by CXR. CT is particularly valuable in diagnosing invasive aspergillosis in pts with neutropenia. The earliest finding is of an enlarging pulmonary nodule surrounded by a hazy rim of edema or hemorrhage (halo sign). With the recovery of the bone marrow, the infarcted central core cavitates, forming the crescent sign. Serum IgG antibodies to Aspergillus are often found in pts colonized with the organism and are nearly universally present in those with aspergilloma.

TREATMENT
Pts with pulmonary aspergilloma and severe hemoptysis may benefit from lobectomy. Systemic therapy is of no value in endobronchial or endocavitary aspergillosis. Treatment with IV amphotericin B (1.0–1.5 mg/kg qd) has resulted in the arrest or cure of invasive aspergillosis when immunosuppression is not severe. Itraconazole (200 mg bid) may be used judiciously by pts who are not severely immunosuppressed and who have indolent or slowly progressive invasive infection.

HISTOPLASMOSIS
EPIDEMIOLOGY/PATHOGENESIS   Histoplasma capsulatum is a dimorphic fungus found in moist surface soil, particularly soil enriched by droppings of certain birds and bats. In the U.S., infection is most common in the southeastern, mid-Atlantic, and central states. Case clusters have occurred among groups of people exposed to dust (e.g., while raking; cleaning dirt- floored chicken coops; spelunking; or cleaning, remodeling, or demolishing old buildings). Infection follows inhalation of the organism and is usually a self- limited condition.
CLINICAL MANIFESTATIONS   In the vast majority of cases, acute pulmonary histoplasmosis is either asymptomatic or mild. Symptoms and signs may include cough, fever, malaise, and CXR findings of hilar adenopathy, with or without areas of pneumonitis. Erythema nodosum and erythema multiforme have been reported in a few outbreaks. Chronic pulmonary histoplasmosis is characterized by subacute onset of productive cough, weight loss, and night sweats. CXRs show uni- or bilateral fibronodular apical infiltrates. In one-third of pts, the disease stabilizes or improves spontaneously. In the remainder, it progresses insidiously and may terminate in death from cor pulmonale, bacterial pneumonia, or histoplasmosis itself. The findings in acute disseminated histoplasmosis, which resemble those in miliary tuberculosis, include fever, hepatosplenomegaly, lymphadenopathy, jaundice, and pancytopenia. Indurated ulcers of the mouth, tongue, nose, or larynx occur in about one-fourth of cases. AIDS pts may develop disseminated disease years after exposure in an endemic area. CXRs are abnormal in 50% of cases, showing discrete nodules or a miliary pattern.
DIAGNOSIS   Culture of H. capsulatum is the preferred diagnostic method but is often difficult. Blood should be cultured by the lysis-centrifugation technique and plates held at 30°C for at least 2 weeks. Cultures of bone marrow, mucosal lesions, liver, and bronchoalveolar lavage fluid are useful in disseminated disease. Sputum culture is preferred for suspected chronic pulmonary histoplasmosis, but visible growth requires 2–4 weeks. Histologic diagnosis is possible but requires considerable expertise. An assay for Histoplasma antigen in blood or urine is commercially available and is useful for diagnosis and monitoring of the response to therapy in AIDS pts with disseminated infection. Serology is of limited value, and histoplasmin skin testing is of no clinical utility.

TREATMENT
Acute pulmonary histoplasmosis does not require therapy. Pts with disseminated or chronic pulmonary histoplasmosis should receive chemotherapy. Amphotericin B (0.6 mg/kg qd) is the agent of choice for pts who are severely ill, who are immunosuppressed, or whose infection involves the CNS. The regimen can be changed to itraconazole (200 mg bid) once improvement becomes evident. The measurement of itraconazole trough blood levels should be considered in pts who may not be absorbing the drug well (e.g., AIDS pts). Itraconazole suspension is better absorbed than the capsule formulation. Immunocompetent pts with mild or moderate disease can immediately be given itraconazole (200 mg bid) and are generally treated for 6–12 months. Ketoconazole (400–800 mg/d) is an alternative for these pts if CNS disease is absent, but side effects are more frequent. A third alternative for immunocompetent pts is amphotericin B (0.5 mg/kg qd) for 10 weeks. Maintenance therapy with itraconazole (200 mg/d) is continued for life in AIDS pts who have responded to 10 weeks of therapy.

BLASTOMYCOSIS
EPIDEMIOLOGY/PATHOGENESIS   Blastomycosis is acquired by inhalation of the dimorphic fungus Blastomyces dermatitidis from soil, decomposed vegetation, or rotting wood. The disease is uncommon in any locality; the majority of cases occur in the southeastern, central, and mid-Atlantic areas of the U.S.
CLINICAL MANIFESTATIONS   A minority of pts have acute, self-limited pneumonia. Most cases, however, have an indolent onset and a chronically progressive course. Fever, cough, weight loss, lassitude, chest ache, and skin lesions are common. The skin lesions enlarge over many weeks from pimples to verrucous, crusted, or ulcerated forms. CXR findings are abnormal in two- thirds of cases, revealing one or more nodular or pneumonic infiltrates. Infection may spread to the brain or meninges. Osteolytic lesions, which may be found in nearly any bone, present as cold abscesses or draining sinuses. Prostatic and epididymal lesions resemble those of tuberculosis.
DIAGNOSIS   The diagnosis is made by culture of B. dermatitidis from sputum, pus, or urine or by wet smear or histology.

TREATMENT
Every pt should receive chemotherapy. As with histoplasmosis, severe disease should be treated with amphotericin B. Skin and noncavitary lung lesions should be treated for 8–10 weeks (cumulative dose, 2.0 g). Cavitary lung disease and disease extending beyond the lungs and skin should be treated for 10–12 weeks (total dose, ³2.5 g). Itraconazole (200 mg bid) is the drug of choice for indolent, nonmeningeal blastomycosis of mild to moderate severity in compliant pts. Ketoconazole (400–800 mg/d) is an effective alternative. Itraconazole or ketoconazole should be given for 6–12 months.

COCCIDIOIDOMYCOSIS
EPIDEMIOLOGY/PATHOGENESIS   Coccidioides immitis is a soil saprophyte with a mold and a spherule form that is found in certain arid regions of the U.S., Mexico, and Central and South America. Infection results from inhalation of windborne arthrospores from soil. Within the U.S., most cases are acquired in California, Arizona, and western Texas.
CLINICAL MANIFESTATIONS   Primary pulmonary coccidioidomycosis is symptomatic in ~40% of cases. When present, symptoms include fever, cough, chest pain, and malaise. Hypersensitivity reactions (e.g., erythema nodosum, erythema multiforme, toxic erythema) sometimes occur. CXRs may show an infiltrate, hilar adenopathy, or pleural effusion. Mild peripheral eosinophilia may be present. Recovery usually begins after several days to 2 weeks of illness and is usually complete. Chronic progressive pulmonary coccidioidomycosis causes cough, sputum production, variable degrees of fever, and weight loss. Disseminated coccidioidomycosis is characterized by malaise, fever, and hilar or paratracheal lymphadenopathy, with serologic evidence of abnormal fungal persistence. With time, lesions appear in bone, skin, subcutaneous tissue, meninges, joints, and other sites. Disseminated coccidioidomycosis can progress rapidly in pts with advanced HIV infection.
DIAGNOSIS   The diagnosis is made by wet smear and culture of sputum, urine, or pus. The suspicion of coccidioidomycosis should be clearly indicated on the requisition to ensure that laboratory personnel exercise appropriate caution. Serology is also helpful; a positive CF test of unconcentrated CSF is diagnostic of coccidioidal meningitis. Seroconversion may be delayed for up to 8 weeks, however. Skin test conversion occurs 3–21 d after the onset of symptoms, but skin testing for the diagnosis of acute infection is of limited utility since results remain positive after remote exposure and may be negative in thin- walled pulmonary cavitary or disseminated disease.

TREATMENT
Pts with disseminated disease should be treated. Pts with severe or rapidly progressive disseminated cases should receive amphotericin B (0.5–0.7 mg/ kg qd). Once improvement occurs or when an infection is relatively indolent, itraconazole (200 mg bid) or fluconazole (400–600 mg/d) may be given. Oral therapy is continued for years. Coccidioidal meningitis is treated with fluconazole (400–800 mg/d) but may also require intrathecal amphotericin B. Single, thin-walled pulmonary cavities are poorly responsive to chemotherapy but tend to close spontaneously.

PARACOCCIDIOIDOMYCOSIS
EPIDEMIOLOGY   Paracoccidioidomycosis, formerly called South American blastomycosis, follows inhalation of spores of Paracoccidioides brasiliensis (a dimorphic fungus). Infection is acquired only in South or Central America or in Mexico.
CLINICAL MANIFESTATIONS   Signs include indurated ulcers of the mouth, oropharynx, larynx, and nose; enlarged and draining lymph nodes; lesions of the skin (particularly that of the genitalia); productive cough, dyspnea, and weight loss; and, in some cases, fever. CXRs most frequently show bilateral patchy infiltrates.
DIAGNOSIS   Cultures of sputum, pus, or mucosal lesions are often diagnostic. Serology may provide an initial clue to the diagnosis.

TREATMENT
Mild cases may be cured by 1 year of oral ketoconazole or itraconazole (200–400 mg/d). More advanced cases are treated with IV amphotericin B followed by an oral agent.

MUCORMYCOSIS
EPIDEMIOLOGY/PATHOGENESIS   Mucormycosis refers to infection by any of several fungal genera, the most common of which in human disease are Rhizopus, Rhizomucor, and Cunninghamella. The organisms are ubiquitous in nature; person-to-person spread does not take place. The disease is largely confined to pts with serious preexisting conditions. Mucormycosis originating in the paranasal sinuses and nose (rhinocerebral mucormycosis) classically occurs in pts with poorly controlled diabetes mellitus. Pts who have undergone organ transplantation, who have a hematologic malignancy, or who have received long-term deferoxamine therapy are predisposed to sinus or pulmonary mucormycosis. GI mucormycosis may occur in a variety of settings, including uremia, severe malnutrition, and diarrheal disease. Regardless of the anatomic location of the infection, vascular hyphal invasion is prominent and leads to hemorrhagic or ischemic necrosis.
CLINICAL MANIFESTATIONS   Disease arising in the nose and paranasal sinuses produces the characteristic clinical picture of low-grade fever, dull sinus pain, and sometimes a thin bloody nasal discharge; following in a few days are double vision, increasing fever, and obtundation. On examination, a unilateral generalized reduction of ocular motion, chemosis, proptosis, a dusky red or necrotic nasal turbinate on the affected side, and a sharply demarcated area of necrosis on the hard palate (strictly respecting the midline) may be present. Invasion of the globe or ophthalmic artery may lead to blindness and that of the orbit to cavernous sinus thrombosis. Pulmonary mucormycosis manifests as progressive, severe necrotizing pneumonia.
DIAGNOSIS   The diagnosis is typically made histologically. The agents of mucormycosis appear as broad, rarely septate hyphae 6–50 µm in diameter. Culture should be attempted, but the yield is low. CT and MRI are helpful in assessing the extent of sinusitis preoperatively and in evaluating the pt postoperatively.

TREATMENT
Regulation of diabetes and reduction of immunosuppression facilitate the treatment of mucormycosis. Craniofacial lesions are treated with extensive surgical debridement and 10–12 weeks of IV amphotericin B at maximal doses (1–1.5 mg/kg qd). Cure may be achieved in 50% of cases.

MISCELLANEOUS MYCOSES
Fusariosis
Fusarium spp. can cause localized or hematogenously disseminated infection, the latter almost exclusively affecting pts with hematologic malignancy and neutropenia. In disseminated infection, an abrupt onset of fever is followed in two-thirds of cases by the appearance of distinctive skin lesions that resemble ecthyma gangrenosum. Blood cultures have been positive in 59% of pts. Amphotericin B should be given, but recovery depends on reduction in the severity of neutropenia.
Malassezia Infection
Malassezia furfur is a component of the normal skin flora but can cause tinea (pityriasis) versicolor or catheter-related sepsis. The latter infection occurs predominantly in pts receiving IV lipid and is cured by catheter removal.
Pseudallescheriasis
Pseudallescheria boydii (also called Petriellidium boydii) is a mold frequently found in soil. Infection may follow inhalation or direct inoculation. The clinical and histologic manifestations of pseudallescheriasis resemble those of aspergillosis, which is much more common. P. boydii can cause fungus balls in the lungs or paranasal sinuses and can invade the globe, the soft tissues, the joints, or the bones after trauma or surgery. In the U.S., P. boydii is the foremost cause of mycetoma, a chronic suppurative infection of subcutaneous tissue. The diagnosis is based on the demonstration of hyphae in tissues. Cultural confirmation is required to distinguish P. boydii from Aspergillus spp. Therapy with itraconazole at the maximal tolerated doses is the regimen of choice; the response is typically poor. Surgical drainage or debridement can be helpful.
Sporotrichosis
Sporotrichosis results from the inoculation of Sporothrix schenckii into subcutaneous tissue via minor trauma. Nursery workers, florists, and gardeners acquire the illness from roses, peat moss, and other plants. Lymphangitic sporotrichosis, by far the most common form, is characterized by the appearance of a nearly painless red papule at the site of inoculation. Over the next several weeks, similar lesions form along proximal lymphatic channels. Spread beyond an extremity is rare. Diagnosis is made by culture of a skin biopsy sample or of draining pus. A saturated solution of potassium iodide, given orally in increasing divided daily doses up to 4.5–9 mL/d for adults, may be curative. Therapy should be continued for a month after the resolution of all lesions. Itraconazole (100–200 mg/d) is an effective and better-tolerated alternative. For extracutaneous disease, a prolonged course of amphotericin B may be curative.
Bibliography

For a more detailed discussion, see Bennett JE: Diagnosis and Treatment of Fungal Infections, Chap. 200, p. 1168; Histoplasmosis, Chap. 201, p. 1171; Coccidioidomycosis, Chap. 202, p. 1172; Blastomycosis, Chap. 203, p. 1173; Cryptococcosis, Chap. 204, p. 1174; Candidiasis, Chap. 205, p. 1176; Aspergillosis, Chap. 206, p. 1178; Mucormycosis, Chap. 207, p. 1179; and Miscellaneous Mycoses and Algal Infections, Chap. 208, p. 1180, in HPIM-15.

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