Estefanía Gartner López Residente de segundo año

Estefanía Gartner López Residente de segundo año
Caso de interés Estefanía Gartner López Residente de segundo año Medicina Interna Universidad del Valle

Datos personales 04/09/19 FI Masculino Sexo 32 años Edad Unión libre
Estado civil Cali O/P Bachillerato completo Escolaridad Taller mecánica Ocupación

“Vengo porque me salió esto en la piel”
Motivo de consulta “Vengo porque me salió esto en la piel”

Histoplasmosis: Cutaneous lesions can take a number of forms from inflammatory folliculitis, molluscum-like papules, verrucous plaques, erythema multiforme-like lesions, vasculitic lesions, exfoliative dermatitis, ulcers and nodular lesions

Enfermedad actual Paciente con cuadro clínico de 20 días de evolución consistente en aparición de múltiples lesiones cutáneas nodulares eritematosas con centro ulcerado, algunas umbilicadas, generalizadas pero de predominio en cara y tórax.

Revisión por sistemas Antecedentes Astenia y adinamia.
Sensación de obstrucción nasal bilateral Antecedentes Patológicos: infección por VIH diagnosticada en Julio 2019. Farmacológicos: atazanavir 300mg/ritonavir 100 mg + emtricitabina 200 mg/tenofovir 300 mg, fluconazol 200 mg/día y trimetoprim/sulfametoxazol 160/800 mg/día desde Julio 2019. Alérgicos: negativo. Hospitalizaciones: negativo. Quirúrgicos: negativo. Toxicológicos: negativo. Traumáticos: negativo. Transfusionales: negativo. Familiares: abuelo hipertenso.

Examen físico 85 lpm 17 rpm 98% con FiO2 21% 120/80 mmHg 36,5 Cº
Escleras anictéricas Mucosas hidratadas Conjuntivas rosadas 17 rpm Sin adenopatías palpables 98% con FiO2 21% Pulmones bien ventilados, sin ruidos agregados. Ruidos cardíacos rítmicos y regulares, sin soplos 120/80 mmHg Abdomen blando, sin dolor a la palpación superficial ni profunda, sin visceromegalias ni masas 36,5 Cº Sin edema, llenado capilar < 2 sg, pulsos distales presentes Peso 60 kg Alerta, orientado, sin déficit motor ni sensitivo. Sin signos meníngeos. Talla 1,69 mt IMC 21

Infección por VIH reciente Inicio de TARV y profilaxis
Lesiones en piel

Manifestaciones mucocutáneas en VIH
In general, noninfectious cutaneous abnormalities are not prognostic of rapid progression of immunosuppression, but they may be specific markers of the stage of HIV disease. For instance, eosinophilic folliculitis virtually always occurs in persons with helper T cell counts below 200. Cutaneous abnormalities may worsen as HIV disease progresses (e.g., seborrheic dermatitis, xerosis),

Fisiopatología Manifestaciones dermatológicas LT ↓CD4
Perfil de citoquinas (Th2) Mimetismo molecular. Sobreexpresión de superantígenos. During the asymptomatic HIV infection, the immunological response preserves a dynamic equilibrium against virus activity, and is also capable of defending against usual or opportunistic intruders; however, the atypical form of stimulation generates various skin and mucosae manifestations. In this stage, the CD4 lymphocyte count decreases, while CD8 count increases and CD4/CD8 ratio inverses. B-lymphocyte polyclonal activation results in -globulin increase, accompanied by autoantibody production and subsequent autoimmune phenomena.1–3 Cytokine levels such as IFN- and TNF- increase while the IL-2 levels of CD4 lymphocytes and the IL-1 levels of dentritic cells and macrophages are decreased. At this stage, manifestations such as seborrhreic dermatitis, psoriasis, xeroderma, and pruritic papular eruption can be seen. As the infection advances, the immunological response weakens both in a quantitative and qualitative manner. The CD4/CD8 ratio decreases dramatically, the reversion of the type of immunological response is becoming typical, and the repertoire of immunological responses diminishes gradually. In advanced stages of HIV disease, manifestations such as seborrheic dermatitis and psoriasis coexist or are generated because of the appearance of opportunistic infections or other disorders. At these stages, OHL, chronic herpes simplex, recurrent herpes zoster, Kaposi’s sarcoma, etc, are also common. The variety of symptoms and signs from the skin during the course of HIV infection is a consequence of the progressing immunodeficiency and therefore indicates the underlying disorder. The use of these manifestations as clinical markers of the disease course is a challenge for clinical praxis. Clinics in Dermatology Y 2004;22:487–498

. In this stage, the CD4 lymphocyte
Activación policlonal de linfocitos B, con aumento en las gamaglobulinas y producción de autoanticuerpos y fenómenos autoinmunes10. Las concentraciones de algunas citoquinas como el IFNγ y el FNTα aumentan, mientras que las IL-1 y 2 disminuyen10. . In this stage, the CD4 lymphocyte count decreases, while CD8 count increases and CD4/CD8 ratio inverses. B-lymphocyte polyclonal activation results in -globulin increase, accompanied by autoantibody production and subsequent autoimmune phenomena.1–3 Cytokine levels such as IFN- and TNF- increase while the IL-2 levels of CD4 lymphocytes and the IL-1 levels of dentritic cells and macrophages are decreased. At this stage, manifestations such as seborrhreic dermatitis, psoriasis, xeroderma, and pruritic papular eruption can be seen. Hoy en día, se sabe que las manifestaciones dermatológicas no ocurren solamente debido a la disminución en los linfocitos T CD4, sino que también debido a un cambio en el perfil de citoquinas hacia un perfil predominantemente T helper 2 (Th2), mimetismo molecular y la sobre-expresión de superantígenos/xenobióticos9. Los pacientes infectados por VIH experimentan una disminución marcada en el número de células de Langerhans, LTCD4, células NK, macrófagos y monocitos; esto explicaría el mayor número de infecciones cutáneas debido a una disminución en los LTCD4 pero además se ha descrito una menor vigilancia por las células de Langerhans9. El cambio en el perfil de citoquinas de T helper 1 (Th1) a Th2 puede explicar la aparición o exacerbación de enfermedades no infecciosas como la dermatitis atópica. Por otro lado, hay inversión de la relación LTCD4/LTCD8 (valor normal > 1); activación policlonal de linfocitos B, con aumento en las gamaglobulinas y producción de autoanticuerpos y fenómenos autoinmunes10. Las concentraciones de algunas citoquinas como el IFNγ y el FNTα aumentan, mientras que las IL-1 y 2 disminuyen10. Manifestaciones dermatológicas asociadas a la infección por VIH/SIDA. Cristián Navarrete -Dechent, Rinna Ortega, Félix Fich. Sochinf. Abril de 2014.

Manifestaciones dermatológicas asociadas a la infección por VIH/SIDA
Manifestaciones dermatológicas asociadas a la infección por VIH/SIDA. Cristián Navarrete -Dechent, Rinna Ortega, Félix Fich. Sochinf. Abril de 2014.

La mayor frecuencia de enfermedades
cutáneas se presenta cuando los linfocitos CD4 se encuentran en cifras inferiores a 250 cel/mm3 10,11 (Tabla 4). . R. Garza-Garza, et al.: Manifestaciones cutáneas del VIH. Gaceta Médica de México. 2014;150 Suppl 2:

Manifestaciones inflamatorias

Síndrome retroviral agudo
Infección inicial por VIH Más del 50% de los pacientes infectados con VIH manifestará signos y síntomas clínicos de infección aguda posterior a un periodo de incubación que varía de dos a seis semanas y persisten un promedio de dos semanas9,13. Esta sintomatología se ha descrito en pacientes de todas las poblaciones de riesgo para el VIH. Se presenta un síndrome viral parecido al descrito en la mononucleosis infecciosa, reportado por primera vez en 1985 y conocido como síndrome retroviral agudo9,14. Los síntomas que se presentan son poco específicos y variables: fiebre de hasta 39 ºC, mialgias, astenia, adinamia y artralgias. En más del 60% de los casos se observa un rash diseminado a tronco y extremidades, generalmente simétrico, maculopapular, eritematoso y no pruriginoso (Fig. 1). También se han reportado tonsilitis, úlceras en cavidad oral y en genitales. Cuando ocurren en mucosa oral pueden causar disfagia severa, provocando pérdida de peso9. En caso de que esta sintomatología persistiera durante más de dos semanas, se relaciona con un peor pronóstico13. Otros signos y síntomas menos frecuentes son: adenopatías no dolorosas, presentes en el 50% de los casos, y síntomas gastrointestinales no específicos, como dolor abdominal transitorio, anorexia, náusea, diarrea y vómito. El VIH se ha aislado en el líquido cefalorraquídeo (LCR) durante la infección primaria, manifestándose con síntomas neurológicos como: cefalea, dolor retroorbitario, fotofobia, radiculopatías y encefalitis13. Es importante considerar este síndrome dentro de los diagnósticos diferenciales de un exantema viral e incluso de reacciones de hipersensibilidad a medicamentos, especialmente cuando se presenta en grupos de riesgo. El tratamiento es sintomático. Puede iniciarse tratamiento antirretroviral con terapia combinada –triple esquema– durante más de 24 semanas, ya que los estudios demuestran que disminuye la carga viral inicial, aumenta el conteo de células T CD4 y retrasa la necesidad de tratamiento antirretroviral en la infección crónica15. 2-4 ss (3 meses) 48-72 h 5 días - semanas «Mononucleosis infecciosa» Infección VIH Manifestaciones dermatológicas asociadas a la infección por VIH/SIDA. Cristián Navarrete -Dechent, Rinna Ortega, Félix Fich. Sochinf. Abril de 2014.

Dermatitis seborréica
Dermatitis atópica Tercera causa después de medicamentos y psoriasis. Seborrheic Dermatitis The occurrence of seborrheic dermatitis (SD) in the general population varies between 2–4%; however, its incidence in patients with HIV is significantly higher.4,5 Seborrheic dermatitis is the most common skin manifestation of HIV disease, occurring most frequently on the scalp, face, and chest. As the disease progresses, the clinical findings worsen and subside after highly-active antiretroviral treatment (HAART).5 It is considered that during the course of the disease, around 85% of patients will at least once manifest SD, although these data seem to have a close link to the type of the studied population and the duration of the follow-up.6,7 Hengge et al reported that 25.3% of HIV patients develop SD lesions prior to HAART.8 Shimizu et al9 reported SD lesions in 38% of Japanese hemophiliac HIV patients, and Jing et al10 reported SD lesions in 20.7% of Malaysian and Chinese HIV patients. In a study by Mirmirani et al,11 SD lesions were found at an increased frequency in seropositive women compared to a control group of seronegative women. In a number of studies, SD manifestations were found at every stage of HIV disease, from the first stages of the disease to the latest. Although the frequency, duration and severity of the rash are common findings at the first stages of the disease, they are basically related to later stages and decreased numbers of CD4 lymphocytes.12 In a study by Alessi et al,13 SD was found in 4.7% of early-stage patients and in 26.7% of full-blown-syndrome patients. Mathes et al6 reported a prevalence of 42% in AIDS-related-complex stage, but 83% in advanced AIDS patients. Disseminated forms of SD, characterized by sternum, back, axillae, and groin lesions, have been reported mainly in advanced disease.5,6,14 In a cohort study by Ippolito et al,15 72 asymptomatic patients were under observation from 1994–95 up to It was concluded that patients suffering from SD had more possibilities of rapid progression to advanced disease. In conclusion, the exacerbation of SD, or its presentation in atypical and severe forms, are related to impending progression of HIV infection, and constitute a clinical index of deterioration of the underlying immunological disorder. -___________________________ As in the West, seborrhea is a very common skin disorder associated with HIV infection in Africa. Seborrheic dermatitis presents as a mildly itchy to nonitchy, scaly rash (Figure 5). Classically, the scalp, auditory canals, postauricular skin, and hair-bearing areas of the face and body (eyebrows, alar creases, beard, central chest, and axillae) are affected with erythema and “greasy” scale. However, in the authors’ experience, seborrhea has a much more varied clinical presentation in Africa. It may spare the face altogether, affecting the scalp, ears, and skin folds such as the axillae, antecubital fossae, and inner thighs. It may also present as a rash with “powdery” scale and very little underlying erythema, favoring the scalp, ears, neck, shoulders, and back. It can occasionally present as erythroderma (full-body erythema and scale). There may be overlap with inverse psoriasis or eczema. Treatment depends on severity. Typically a combination of topical antifungal drugs directed at Pityrosporum yeast and low- to midpotency topical steroids for inflammation will lead to improvement. _________________ Psoriasis Clinics in Dermatology Y 2004;22:487–498

Erupción papular pruriginosa
Foliculitis eosinofílica Erupción papular pruriginosa Clinics in Dermatology Y 2004;22:487–498

Manifestaciones asociadas a medicamentos

Reacciones adversas a medicamentos
Riesgo ↑ x 100 En el 22% de los pacientes con VIH. Erupción morbiliforme: tronco y extremidades. Eritema multiforme. Eritema fijo medicamentoso. Síntomas sistémicos (20%) HLA-B5701 (Abacavir) NET: mortalidad (55%) Approximately 20% of cases are associated with systemic symptoms, such as fever, headache, myalgia, and arthralgia. Drug reaction with eosinophilia and systemic syndrome may develop in patients treated with abacavir. ________________ Trimethoprim-sulfamethoxazole is the treatment of choice for Pneumocystis carinii infection. However, 1–2 weeks after initiating therapy, up to 50%–60% of HIV-infected patients may develop a morbilliform rash [113]. Rarely, patients can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis. Foscarnet is clearly indicated for acyclovir-resistant mucocutaneous HSV infections, but the many side effects limit its role as a primary antiviral agent in other environments. Dermatologic side effects include the development of genital ulceration in 5%–30% of patients, most commonly located on the periurethral glans penis [114]. This contact dermatitis, thought to be secondary to urine concentration of the drug, may be avoided with adequate hydration and proper hygiene [10]. The nucleoside reverse transcriptase inhibitors zidovudine and abacavir have significant cutaneous side effects. Zidovudine has been associated with nail dyschromia characterized by blue or brown longitudinal bands that spread from the proximal to distal nail plate 4-8 weeks after initiating therapy [115,116]. Other cutaneous side effects of zidovudine include skin pigmentation, pruritis, urticaria, and a nonspecific maculopapular rash [117]. Abacavir has been associated with a hypersensitivity reaction approximately 10 days after initiating treatment in 5% of patients. The syndrome is characterized by an evolving maculopapular rash, fever, and malaise. Remission occurs with cessation of the abacavir treatment, though rechallenge may produce a more severe and possibly fatal reaction [117]. The nonnucleoside reverse transcriptase inhibitors nevirapine and delavirdine sometimes result in a cutaneous eruption. Approximately 50% of patients taking nevirapine transiently experience a pruritic maculopapular rash [118–120]. Starting with a low dose and titrating to desired levels sometimes avoid this side effect. Patients having a severe rash or any rash with constitutional symptoms such as fever should permanently discontinue the medication [118,121]. Rarely, patients may develop Stevens- Johnson syndrome [122]. Finally, protease inhibitors have also been associated with cutaneous reactions. Both indinavir and amprenavir may produce a rash. Nearly one third of patients taking amprenavir experience a maculopapular rash. Stevens-Johnson syndrome occurs in 1% of these patients [117]. _____________________ Drug Eruptions With the roll-out of antiretroviral therapy in Africa, associated drug eruptions occur commonly. Two types of drug eruptions that deserve special mention are Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and single or multiple fixed-drug eruptions (Figure 9). In the case of simple drug eruptions that are not life-threatening or incapacitating to the patient, clinicians may elect to “treat through” the symptoms with topical steroids and antihistamines. In this situation, patients should be monitored closely for the development of blisters, mucous membrane involvement, or systemic symptoms. The overwhelming majority of serious drug eruptions in East Africa are caused by sulfonamides or nevirapine (Figure 10). Women starting nevirapine treatment at CD4+ counts above 250 cells/μL are particularly at risk of severe hypersensitivity reactions.3,4 SJS/TEN is often easily recognized, as most patients present for care late in the course of the disease, with erosion of mucous membranes (particularly the lower lip) and skin. Systemic steroid use is controversial; the authors do not recommend treatment with oral steroids unless used within the first 24 hours of symptom onset. Treatment is discontinuation of the offending drug as well as all other nonessential oral medications, and supportive care. Fixed-drug eruptions typically present as strikingly round and sharply demarcated, intensely hyperpigmented patches (Figure 11). They may be single or multiple and located anywhere on the body, but the lips and genitals are frequent sites of involvement. The eruption may occur in the same place with each exposure or affect a new area of skin. In the authors’ experience, the overwhelmingly common culprit is an antibiotic, most often a sulfonamide, although a host of other drugs may cause this eruption. In regions where antibiotics are available over the counter, fixed-drug eruptions occur frequently._________ ________________________ Reacciones adversas a fármacos Los pacientes con VIH son susceptibles a presentar reacciones adversas a fármacos, lo cual ocurre hasta en el 22% de los pacientes118. Estas reacciones son la principal causa de eritrodermia en los pacientes con VIH. Las manifestaciones cutáneas más comunes involucran un rash eritematoso, morbiliforme, en ocasiones confluente que abarca principalmente tronco y extremidades (Fig. 20); en casos más severos se presenta el síndrome de Stevens-Johnson y la necrólisis epidérmica tóxica (NET), con una incidencia de 1-2 casos por cada 1,000 individuos119 y una mortalidad de hasta el 55% en el caso de NET120. La alta prevalencia de estas reacciones de hipersensibilidad a fármacos se debe a la gran cantidad de medicamentos a los que están expuestos (antirretrovirales, antibióticos, antivirales, entre otros, que se administran de forma terapéutica o profiláctica), aunado a que su predisposición se aumenta por la afección en la inmunidad118. Algunas infecciones virales también pueden predisponer a estas reacciones, como en el caso de la administración de penicilina al cuadro de mononucleosis infecciosa asociada a CMV o al virus de Epstein-Barr. Los medicamentos que comúnmente causan reacciones en estos pacientes incluyen: aminopenicilinas, clindamicina, rifampicina, trimetoprima-sulfametoxazol y anticonvulsivantes, entre otros. Los diferentes fármacos utilizados en el tratamiento antirretroviral son responsables de manifestaciones mucocutáneas diversas. La zidovudina, el primer inhibidor de la transcriptasa reversa análogo de nucleósidos aprobado por la Food and Drug Administration, se caracteriza por causar hiperpigmentación proximal ungueal en bandas longitudinales de color azul, gris o café que aparecen tras un mes de tratamiento118. El abacavir es otro inhibidor de la transcriptasa reversa análogo de nucleósidos que causa reacciones de hipersensibilidad hasta en el 8% de los pacientes. En la piel se observa un rash maculopapular o una reacción urticariforme aproximadamente días después de empezar el tratamiento con el medicamento. Además de esto, se acompaña de diarrea, vómito, dolor abdominal, mialgias, artralgias, fiebre y síntomas respiratorios. Se ha asociado también a NET118. El inhibidor de transcriptasa reversa no análogo de nucleósidos efavirenz también es responsable de reacciones cutáneas, principalmente maculopapulares. El indinavir es un inhibidor de proteasa con múltiples reacciones cutáneas, como síndrome de hipersensibilidad, alopecia, paroniquia, rash maculopapular y síndrome de Stevens-Johnson118. HIV Dermatology in Africa Volume 18 Issue 1 February/March 2010

(no infecciosas-no neoplásicas)
Los pacientes con infección por VIH tienen un mayor riesgo de experimentar reacciones adversas a medicamentos (RAM) mediadas inmunológicamente en comparación a la población sana, debido a disregulación de su sistema inmune y al gran número de fármacos que consumen4. Las toxicodermias ocurren en aproximadamente 3 a 22% de estos pacientes4,23,25. De esta misma manera, el uso de TARV en pacientes infectados por VIH no está exento del riesgo de desarrollar una RAM inmunológica. Los efectos adversos de la TARV incluyen varios puramente dermatológicos, como por ejemplo: efectos retinoide-símil (paroniquia, xerosis cutánea intensa, alopecia, granuloma telangiectásico y queilitis), lipodistrofia (caracterizado por redistribución de la grasa corporal con pérdida de grasa periférica, aumento de la grasa central, hipertrofia mamaria y aumento de la grasa dorso-cervical asociado a anormalidades metabólicas), erupción morbiliforme (Figura 2) y síndrome de Stevens-Johnson; entre otros4. En la Tabla 2 se resumen los efectos adversos dermatológicos más comunes de la TARV según la familia del fármaco. Manifestaciones dermatológicas asociadas a la infección por VIH/SIDA. Cristián Navarrete -Dechent, Rinna Ortega, Félix Fich. Sochinf. Abril de 2014.

Exantema morbiliforme
Penicilinas Clindamicina Rifampicina Antconvulsivantes TMP / SMX Hasta en el 47% Exantema morbiliforme Dermatitis reaccional medicamentosa en un paciente con VIH en tratamiento con trimetoprima-sulfametoxazol . R. Garza-Garza, et al.: Manifestaciones cutáneas del VIH. Gaceta Médica de México. 2014;150 Suppl 2: HIV Dermatology in Africa Volume 18 Issue 1 February/March 2010

Síndrome de reconstitución inmune

Síndrome de reconstitución inmune
Inicio de la TARV Capacidad de respuesta inmune Reconocimiento de múltiples microorganismos Empeoramiento paradójico del paciente Prevalencia hasta de 25% En las primeras 8 semanas de TARV Exacerbación de condiciones inflamatorias e infecciosas Hasta primeros 3 meses de iniciada la TARV Síndrome de reconstitución inmunológica (SRI) Se presenta con posterioridad al inicio de la TARV y tiene un amplio espectro de manifestaciones. Ocurre debido a que el paciente recupera su capacidad para desarrollar una respuesta inmunológica y comienza a reconocer múltiples microorganismos26. La respuesta inflamatoria puede ser a agentes infecciosos, como micobacterias, hongos oportunistas y diferentes tipos de virus (herpes simplex, virus papiloma humano) presentes al momento del inicio de los antivirales, produciéndose un empeoramiento paradojal del paciente pese al aumento en el recuento de LTCD426. Además, existen múltiples reportes de casos que muestran exacerbaciones de infecciones subclínicas a otros agentes infecciosos no mencionados. Sumado a esto, pueden empeorar patologías inflamatorias como la sarcoidosis, FE y DA26. Algunas series han mostrado una prevalencia de SRI de 25%; en general ocurre en pacientes de alto riesgo durante las primeras ocho semanas de iniciada la TARV: aquellos que inician TARV con un recuento de LTCD4 bajo (menor a 200 céls/mm3) y aquellos con infecciones subclínicas al momento de iniciar la terapia24,26. Manifestaciones dermatológicas asociadas a la infección por VIH/SIDA. Cristián Navarrete -Dechent, Rinna Ortega, Félix Fich. Sochinf. Abril de 2014.

Dermatologic Manifestations of the Immune
Reconstitution Inflammatory Syndrome Fig. 1. Fatal disseminated herpes zoster infection during HAART. This 27-year-old man with previous tuberculous meningitis and a baseline CD4 cell count of 53 cells/mL had been receiving HAART (stavudine, lamivudine, and efavirenz) for 2 months when he presented with C2/3 dermatomal varicella-zoster that disseminated with pulmonary involvement. He was treated with intravenous acyclovir, and HAART was continued. He died of respiratory failure. Dermatol Clin 24 (2006) 549–570

Fig. 2. Mollsucum contagiosum IRIS. This 25-year-old
woman with World Health Organization stage 4 HIV and a baseline CD4 cell count of 31 cells/mL had facial molluscum contagiosum preceding the introduction of HAART, but 2 months after starting HAART (stavudine, lamivudine, and nevirapine) she developed multiple new lesions. Dermatol Clin 24 (2006) 549–570

Fig. 4. Ulcerative cryptococcal cutaneous lesions unmasked by HAART
Fig. 4. Ulcerative cryptococcal cutaneous lesions unmasked by HAART. This 31-year-old man with World Health Organization stage 4 HIV started HAART (stavudine, lamivudine, and efavirenz) with a CD4 cell count of 16 cells/mL. After 7 months of HAART his CD4 cell count had risen to 80 cells/mL. He was referred to the authors’ unit after 8 months of HAART in a wasted condition with multiple deep cutaneous ulcers over his trunk (A and B), limbs (B) and right eyelid, which he reported had developed 1 month after starting HAART. Histology of an ulcer biopsy demonstrated encapsulated yeasts with budding on a mucicarmine stain (C), and Cryptococcus neoformans was cultured. He had no past history of cryptococcosis. Fungal blood and cerebrospinal fluid cultures were negative. He responded to oral fluconazole. Presumably, these lesions represented an unmasking IRIS directed at cryptococcal organism that had ceded from the blood into subcutaneous tissues while he was profoundly immunocompromised. Dermatol Clin 24 (2006) 549–570

Manifestaciones neoplásicas

Sarcoma de Kaposi (SK) Cáncer anal
Manifestaciones dermatológicas asociadas a la infección por VIH/SIDA. Cristián Navarrete -Dechent, Rinna Ortega, Félix Fich. Sochinf. Abril de 2014.

Manifestaciones infecciosas
Manifestaciones infecciosas asociadas a VIH Las infecciones son una causa frecuente de manifestación muco-cutánea de la infección por VIH8. Múltiples agentes bacterianos, virales, fúngicos o parasitarios pueden producir infecciones en este grupo de pacientes. Bacterianas El grupo principal de bacterias que cause infecciones cutáneas son las especies grampositivas; de ellas, la principal es Staphylococcus aureus. En este grupo de pacientes debe recordarse la posibilidad de que la infección sea causada por S. aureus resistente a meticilina (SARM)37, llegando a una tasa de portación de 8,2% comparado con 3% en la población sin VIH pero con los mismos factores de riesgo. De estos pacientes seropositivos para VIH, colonizados con SARM, 55% desarrolló una infección posterior30. Del mismo modo, la incidencia de SARMadquirido en la comunidad (SARM-AC), es seis veces más frecuente en pacientes con infección por VIH. Además, la recurrencia de estas piodermias es alta, con recidivas de 41% a cuatro meses32. El número de infecciones y la tasa de recurrencia disminuye significativamente con la disminución de la carga viral32. Las formas más comunes de presentación son la foliculitis, el impétigo y la celulitis; también puede manifestarse como ectima, forúnculos, ántrax y abscesos. Suelen tener un curso localmente agresivo, que puede llegar a cuadros de sepsis y bacteriemia. Se localizan en las extremidades inferiores, glúteos y escroto, con mayor frecuencia que en las extremidades superiores y la cara32. No se ha encontrado resistencia a cotrimoxazol en las series publicadas de SARM-AC37. Pseudomonas aeruginosa puede causar infecciones primarias tales como la infección de catéteres o en las regiones ano-genital y axilar. Además, puede causar infección secundaria de otras dermatosis como el sarcoma de Kaposi o por diseminación hematógena a la piel, cuadro conocido como ectima gangrenoso. Micobacterias La tuberculosis (TBC) es una infección oportunista común en la enfermedad por VIH38,39. La TBC cutánea representa sólo 1 a 2% de los casos de TBC y puede ocurrir por inoculación cutánea primaria o por diseminación sistémica. La prevalencia de TBC cutánea podría estar aumentando en los casos de pacientes con infección por VIH40. La expresión clínica es diversa pero se puede presentar como pápulas y placas costrosas induradas diseminadas en los casos de diseminación cutánea desde una TBC sistémica pulmonar o meníngea, cuadro que es denominado TBC miliar cutánea generalizada aguda. Se incluye dentro del diagnóstico diferencial de lesiones “moluscoides” que se detallará más adelante41. Por otro lado, las micobacterias atípicas o micobacterias no tuberculosas son bacilos ácido-alcohol resistentes, ubicuos en la naturaleza. Incluyen a las siguientes especies: M. avium complex, M. bovis, M. kansasii, M. marinum, M. malmoense, M. ulcerans, M. chelonae, M. fortuitum y M. abscessus, entre otros. Los últimos tres corresponden a especies de crecimiento rápido según la clasificación de Runyon42,43. Su incidencia está aumentando, en parte por la diseminación del VIH42. El compromiso cutáneo se caracteriza por abscesos, forúnculos, tractos profundos que drenan hacia la piel o seromas indolentes43. Además, se pueden presentar como placas o nódulos verrucosos, ulcerados, en las extremidades superiores, sobre todo en el caso de M. marinum39. Se debe sospechar infección por micobacterias atípicas en cualquier paciente con lesiones nodulares profundas, principalmente con posterioridad a la exposición de ambientes húmedos, a trauma local o masoterapia43. El agente micobacteriano más frecuente distinto a Mycobacterium tuberculosis que provoca enfermedad en SIDA avanzado es el complejo Mycobacterium avium complex (MAC), aunque rara vez produce manifestaciones cutáneas44. Las lesiones cutáneas por MAC, a diferencia de las causadas por TBC, se desarrollan en etapas más tardías de la infección por VIH41. Angiomatosis bacilar La angiomatosis bacilar y peliosis hepática bacilar son expresiones poco frecuentes de infecciones causadas por Bartonella henselae y B. quintana; se producen más comúnmente en etapa avanzada de SIDA (menos de 200 LTCD4/mm3)10. Se caracterizan por lesiones angioproliferativas que semejan hemangiomas en cereza, granulomas piógenos o sarcoma de Kaposi, como pápulas cupuliformes, nódulos o placas de color rojo a violáceas la mayoría de las veces diseminadas (Figura 5)45. Los antimicrobianos de elección son macrólidos o doxiciclina. En nuestra experiencia, se han usado azitromicina y ciprofloxacina con buena respuesta45. Sífilis Existe una asociación epidemiológica entre sífilis e infección por VIH, las úlceras genitales favorecen la transmisión de Treponema pallidum y éste a su vez, la transmisión del VIH46. Pese a que la incidencia de la sífilis iba en disminución, la llegada del VIH ha vuelto a aumentar las tasas de esta enfermedad32,47,48. Son factores de riesgo para adquirir sífilis: ser homosexual, tener historia de una infección de transmisión sexual, tener múltiples parejas sexuales y participar en sexo anal-oral-genital sin protección30. Clínicamente se puede presentar de manera atípica como sífilis primaria con chancro más grave y doloroso, en localizaciones inusuales (Figura 6); como chancros múltiples en 25% de los pacientes, o incluso llegando a chancros agresivos con perforaciones de labios mayores o prepucio47. Algunos autores han reportado una mayor demora en la curación del chancro47,48 Aproximadamente, 25% de los pacientes con sífilis primaria, no tratada, progresarán a sífilis secundaria47. Esta etapa de la sífilis se manifiesta, en 70% de las veces, como un rash pápulo-escamoso generalizado con compromiso planto plantar (Figura 7); sin embargo, puede manifestarse como sífilis maligna en 7% de los pacientes infectados con VIH y sífilis: El cuadro se caracteriza por erupción pápulo-escamosa difusa, con pústulas, nódulos y úlceras con presencia de vasculitis necrosante47,49. Los criterios diagnósticos incluyen títulos de tests no treponémicos muy elevados, reacción de Jarisch-Herxheimer y una clara respuesta a tratamiento47. En algunos casos, se pueden presentar lesiones de sífilis primaria y secundaria concomitantemente e incluso de sífilis primaria y terciaria en un mismo paciente47,48. Otras manifestaciones incluyen la alopecia en 3 a 7% de los pacientes y las lesiones mucosas, entre muchas otras que escapan a esta revisión47. El diagnóstico se realiza de la misma forma que en pacientes no infectados por VIH pero existen algunos reportes de casos con serologías aberrantes incluyendo la “sífilis seronegativa” (test no-treponémicos y treponémicos falsamente negativos). Muchos de estos falsos negativos pueden deberse a fenómenos de “prozona” causado por anticuerpos a títulos muy altos47. Del mismo modo, 18% de los pacientes con sífilis e infección por VIH, no normalizan sus títulos de tests no treponémicos al año de seguimiento pese a haber recibido tratamiento adecuado, generando casos de test no treponémicos falsamente positivos47. La neurosífilis es un tema que escapa a este capítulo; sin embargo, consideramos importante realizar una punción lumbar en pacientes con sífilis que presenten: síntomas y signos neurológicos; evidencia de enfermedad terciara activa; falla a tratamiento sin evidencia clara de reinfección y en pacientes con sífilis y VIH asintomáticos neurológicamente y que tengan VDRL/RPR > 1: 32 ó LTCD4 < 350 céls/mm3 48,50,51. El riesgo de encontrar un LCR alterado se incrementa aún más si se realiza en pacientes con VDRL/RPR > 1: 32 y LTCD4 < 350 céls/ mm3 51. Bencil-penicilina sigue siendo el antimicrobiano de elección, aun en este grupo de pacientes. Azitromicina, que aparece como alternativa terapéutica en pacientes alérgicos a penicilina, no debe ser utilizada en pacientes con infección por VIH debido a que se han reportado tasas de resistencia bacterianas mayores a 33%47. La reacción de Jarisch-Herxheimer ocurre con mayor frecuencia en pacientes con sífilis maligna y se discute si su incidencia está elevada per se en todos los pacientes con infección por VIH47,48. Infecciones virales Los virus son los principales patógenos que causan infecciones oportunistas en la enfermedad del VIH, ya sea por activación de la infección subclínica (VPH, Poxvirus) o por reactivación de infecciones latentes (herpes simplex tipo 1 [HSV-1], herpes simplex tipo 2 [VHS-2], virus varicela zoster [VVZ], citomegalovirus [CMV], virus de Epstein-Barr [VEB] y el virus herpes humano tipo 8 [VHH-8]). En varios estudios, el herpes zoster (HZ) aparece como una de las principales y primeras manifestaciones en los pacientes seropositivos para VIH, llegando hasta 28%7,52. En general, la incidencia de estas infecciones virales se ha reducido notablemente con la TARV, salvo las causadas por el VPH. Virus herpes simplex (VHS) tipos 1 y 2 El VHS continúa siendo la causa mundial más frecuente de úlcera genital; en pacientes con infección por VIH puede presentarse de manera atípica o extensa, de forma ulcerativa o hipertrófica-tumoral y de manera crónica (Figura 8)32,53. Existe reactivación subclínica de VHS en pacientes con infección por VIH; menos de 10% de las reactivaciones presentan síntomas. Estudios demuestran que la infección aguda y recurrencias por VHS pueden estimular la replicación del VIH y se asocia a un aumento de dos a cuatro veces del riesgo de transmisión del VIH32. Curiosamente, el tratamiento supresor herpético no reduce el riesgo de transmisión del VIH; pero sí reduce la aparición de las úlceras herpéticas causadas por VHS-2, en 73%54. En los pacientes seropositivos para VIH con recuentos > 100 LTCD4/mm3, la infección por VHS 1 y 2 se manifiesta con el cuadro clínico clásico, auto limitado y menos de dos semanas de duración. En la infección por VIH más avanzada, se observa aumento en el número y tamaño de las lesiones, recurrencias más graves y frecuentes, con vesículas y úlceras más dolorosas y profundas, que curan más lentamente e incluso presentan lesiones verrugosas, crónicas, con o sin ulceración. Las infecciones herpéticas crónicas ocurren en 0,2% de los pacientes con infección por VIH y pese a que se definen como aquellas que duran más de un mes, no es raro que duren meses o incluso años, pasando desapercibidas por largos períodos de tiempo53. Puede haber presentaciones atípicas, localizadas en la zona inferior de la espalda, glúteos y regiones perianales, con extensiones hasta de 20 cm de diámetro. En pacientes con patologías cutáneas crónicas como dermatitis de contacto, dermatitis atópica o psoriasis, entre otras, puede presentarse una erupción herpética diseminada conocida como “eccema herpético” o “erupción variceliforme de Kaposi”. La mayoría de estos cuadros de herpes diseminado ocurre por el VHS tipo 155. No está claro si la infección por VIH produce aumento en la incidencia de esta patología56. Infección por virus varicela zoster (VVZ) Los episodios de herpes zoster (HZ) por reactivación del VVZ en pacientes con infección por VIH ocurren con una incidencia 10 veces mayor en comparación a la población general32. Cabe destacar, que el HZ ocurre en etapas precoces de la infección por VIH y que muchas complicaciones como el HZ diseminado y el síndrome de Ramsay-Hunt ocurren incluso con recuentos de LTCD4 elevados. Todo esto sugiere una disfunción de las células T inducida por la infección por VIH que, pese a buen control virológico, jugarían un rol importante en la relación entre VVZ y VIH7. Otras manifestaciones de la infección por VVZ en paciente infectados por VIH son la varicela grave que puede ser adquirida de novo o por una reactivación en pacientes con antecedentes de varicela o HZ; en ellos no se presenta con forma dermatomérica y tiene compromiso sistémico frecuente con riesgo vital57. Otra forma de presentación es como HZ diseminado (más de 20 lesiones fuera del dermatoma o con compromiso de dermatomas anexos), HZ necrótico y HZ recurrente58. Existen casos de HZ crónico (duración de más de un mes) que pueden ser der- Figura 8. Herpes simplex tipo 2 perianal. matoméricos o encontrarse sin un patrón de distribución característico, lo que sugiere una forma de diseminación vascular más que neural en estos pacientes53. Virus del papiloma humano (VPH) La infección por VPH, manifestada como verrugas y condilomas acuminados (Figura 9), es muy frecuente en los pacientes seropositivos para VIH. Aproximadamente 13% de los pacientes con infección por VIH presentarán patología ano-rectal; de este grupo 92% corresponde a condilomas perianales59. El tratamiento de los condilomas perianales es muy importante debido al riesgo de desarrollar cáncer anal, como ya fue comentado32. Lamentablemente, la incidencia de estas lesiones no tiende a disminuir con la TARV, por lo que deben tratarse activamente. Existen múltiples tratamientos descritos para los condilomas y las verrugas genitales60. En un estudio, el tratamiento con imiquimod al 5%, tres veces a la semana durante 16 semanas, disminuyó la presencia de ADN de VPH de alto riesgo en aproximadamente 50%; sin embargo, el clearence de las lesiones fue sólo de 32%61. Epidermodisplasia verruciforme adquirida La epidermodisplasia verruciforme (EV) es una genodermatosis autosómica dominante rara. Se trata de una inmunosupresión que confiere susceptibilidad a la infección con VPH que no infectan individuos sanos; éstos corresponden al VPH-5 y VPH-8 entre otros La enfermedad se caracteriza por máculas hipopigmentadas (pitiriasis versicolor símiles) en el tronco, extremidades y cara durante la niñez y lesiones parecidas a las verrugas planas en zonas fotoexpuestas. La EV confiere un alto riesgo de desarrollar un carcinoma espinocelular en zonas fotoexpuestas debido a la infección por VPH, lo cual ocurre en 30 a 60% de los pacientes62. Hace algunos años, se describieron pacientes con infección por VIH, sin las alteraciones genéticas clásicas de la EV (mutaciones en los genes EVER 1 y 2), que desarrollaban lesiones similares: esta enfermedad, por tener un patrón común con la EV clásica de déficit en la inmunidad celular, se llamó EV adquirida (EVA)62. No hay que confundir los pacientes con EVA con los pacientes con EV clásica que adquieren la infección por VIH de manera tardía en su vida. La EVA también ha sido descrita en otras inmunosupresiones63. Se ha propuesto que esta entidad es más frecuente en pacientes infectados por el VIH de manera vertical o en etapas precoces en su vida, por lo tanto se trataría de pacientes jóvenes. Esto ocurriría debido a que no alcanzarían a generar inmunidad contra este grupo especial de genotipos de VPH; inmunidad que probablemente exista en pacientes adultos que contraen la infección por VIH62. El potencial maligno de la EVA no ha sido demostrado aún, no se sabe si esto se deba a falta de seguimiento (los pacientes con EV clásica desarrollan carcinoma espinocelular en la cuarta década de vida) o es debido a que este riesgo no existe en la EVA. No disponemos de un tratamiento establecido para la EVA pero se ha intentado retinoides, interferón, imiquimod y terapia fotodinámica, todos con reportes en casos aislados62. Molusco contagioso Esta infección viral benigna, autolimitada, se presenta en los niños y adultos jóvenes y es causada por un poxvirus. Ocurre en aproximadamente 10 a 20% de los pacientes con infección por VIH y es un signo clínico de progresión de la infección por VIH y bajos recuentos de LTCD465. En este grupo de pacientes pueden ser múltiples y extensos, de mayor tamaño, confluentes, desfigurantes (diámetro mayor a 1 cm, verrugosas), de ubicación atípica (cabeza y cuello) y resistentes a los diferentes tratamientos (Figura 10)66. El diagnóstico diferencial de las pápulas umbilicadas incluye clásicamente infecciones por hongos como la criptococosis y la histoplasmosis67; sin embargo, este tipo de lesiones se ha asociado también a otras infecciones oportunistas fúngicas y bacterianas como Blastomyces, Coccidiodes, Paracoccidiodes, Sporothrix, micobacterias atípicas, B. hensenlae, y patologías neoplásicas como el SK67. Leucoplasia vellosa oral (LVO) Es una lesión de la mucosa oral y de la lengua causada por el virus de Epstein Barr (VEB). Se caracteriza por la aparición de una o varias placas blanquecinas, no desprendibles, usualmente ubicadas en los bordes laterales de la lengua (Figura 11). Su superficie es usualmente corrugada o puede plegarse formando proyecciones elevadas (vellosas) generalmente bilaterales, pero asimétricas y asintomáticas10. Puede simular otras lesiones blanquecinas incluyendo la leucoplasia, liquen plano, carcinoma espinocelular, lengua geográfica y la candidiasis oral, sin compromiso de otras mucosas. Se presenta con frecuencias variables de hasta 25% en pacientes con infección asintomática por VIH y aumenta su frecuencia al disminuir el recuento de LTCD410. No es una enfermedad exclusiva de la infección por VIH debido a que se ve también en pacientes receptores de trasplantes. Son factores de riesgo para la LVO ser hombre, recuento de LTCD4 < 200 céls/mm3 y alta carga viral. El diagnóstico se puede realizar con microscopia electrónica e hibridación in situ del ADN del VEB. Generalmente se resuelve con la TARV, lo que la hace un buen indicador de la actividad de la enfermedad y de falla a tratamiento10. El tratamiento puede realizarse con podofilina. Otros tratamientos que han mostrado respuesta son la cirugía y los antivirales orales e intravenosos68. Infección por citomegalovirus (CMV) Las manifestaciones cutáneas aisladas del CMV son poco frecuentes, incluso en pacientes con infección por VIH. Pueden imitar a otras erupciones cutáneas, especialmente las herpéticas. La presentación más común en pacientes seropositivos para VIH son las úlceras extensas en la región perineal con tejido de granulación69. La biopsia de piel mostrará infiltración perivascular linfohistiocitaria, con o sin vasculitis; el endotelio de los pequeños vasos dérmicos mostrará células de gran tamaño con inclusiones intranucleares características, con o sin halo. También se asocia a erupciones máculo-papulares similares a las secundarias a VEB y a rash morbiliforme secundario a la administración de amoxicilina; la infección crónica por CMV o VEB podría explicar el aumento de las RAM en pacientes con VIH69. Infecciones fúngicas La infección por VIH produce una disregulación inmunológica con un predominio de citoquinas Th2, disminuyendo la capacidad de los macrófagos para eliminar microorganismos intracelulares; esto lleva a una mayor incidencia de infecciones por hongos70. Candidiasis Desde el comienzo de la epidemia del SIDA se determinó la infección por Candida spp como un marcador de falla inmunológica (Figura 12). Además, es la infección oportunista más frecuente en muchas series, llegando a 90% de prevalencia7,8,10,70. Es causada principalmente por Candida albicans pero también por C. glabrata, C. tropicalis, C. krusei y C. parapsilosis. Esto cobra importancia debido a que C. glabrata y C. krusei son resistentes a fluconazol70. Puede ocurrir en cualquier momento de la enfermedad pero la inmunodeficiencia y disminución en los recuentos de LTCD4 aumentan su incidencia10,70. El uso de TARV disminuye la prevalencia de candidiasis orofaríngea. La candidiasis esofágica se describe como una complicación de la candidiasis oral; en pocas ocasiones puede llevar a hemorragia digestiva alta con perforación de la pared gástrica o intestinal70. La candidiasis diseminada es muy infrecuente y se presenta en usuarios de drogas intravenosas, como una foliculitis71,72. Otras manifestaciones incluyen onicomicosis con paroniquia, onicodistrofia, intértrigo y candidiasis vaginal recurrente crónica; es inusual el compromiso sistémico y la fungemia70. Figura 11. Leucoplasia vellosa oral. Dermatofitosis Causadas por Tricophyton, Microsporum y Epidermophyton. De éstos, el hongo más frecuente, al igual que en inmunocompetentes, es T. rubrum. En los pacientes con infección por VIH, las infecciones por dermatofitos pueden ser asintomáticas extensas (Figura 13), diseminadas con compromiso de las cuatro extremidades, de múltiples uñas (Figura 14), de presentación atípica y con mala respuesta a tratamiento. El compromiso dérmico profundo por dermatofitos es poco frecuente y es un marcador de inmunosupresión. Estas lesiones aparecen en áreas con micosis superficiales crónicas y se presentan como ulceraciones múltiples y nódulos fluctuantes. El granuloma de Majocchi (perifoliculitis granulomatosa nodular) es un ejemplo de compromiso dérmico por dermatofitos. Se caracteriza por la presencia de nódulos eritemato-violáceos firmes asociado a onicomicosis, tinea corporis o tinea pedis70. Por otro lado, este grupo de pacientes puede tener infecciones por hongos no dermatofitos como Fusarium spp, Acremonium spp, Aspergillus spp, Scopulariopsis spp, Onychocola spp, entre otros. Este grupo de hongos puede diseminarse y causar micosis invasoras sistémicas (pulmonares, endoftalmitis, etc.) y fungemia, por lo cual deben ser tratadas73. Infecciones fúngicas invasoras Pueden surgir por invasión local de piel o mucosa o por activación de un foco de infección pulmonar latente de criptococosis, histoplasmosis, coccidiomicosis, esporotricosis o penicilliosis y difundir a distintos órganos (pulmones y meninges clásicamente) y piel, en 5 a 15% en personas con enfermedad avanzada por VIH (recuentos de LTCD4 < 50 céls/mm3). Las manifestaciones cutáneas más frecuentes son semejantes al molusco contagioso67,74. Criptococosis Enfermedad causada por la levadura Cryptococcus neoformans. Su forma diseminada es una de las micosis subcutáneas fatales más comunes en pacientes con infección por VIH/SIDA; se consideran pacientes en riesgo aquellos con LTCD4 < 100 céls/mm3 74. Se contagia generalmente por inhalación de las levaduras desde las palomas u otras aves y genera focos pulmonares. Las lesiones cutáneas se presentan en 10% de los pacientes con compromiso sistémico (secundario a siembra hematógena desde focos pulmonares) y se localizan con mayor frecuencia en la cabeza y el cuello, pudiendo ser generalizadas67. La morfología cutánea más frecuente es tipo molusco contagioso (pápulas o nódulos color piel-rosados, umbilicados), pudiendo tener necrosis o ulceración central67; otras lesiones cutáneas en la criptococosis son las pústulas, celulitis, ulceración, paniculitis, púrpura palpable, abscesos subcutáneos, placas vegetantes y lesiones similares a pioderma gangrenoso67,75. La infección cutánea primaria es excepcional y es usualmente secundaria a trauma local en ambientes donde el hongo es prevalente; produce un patrón linfangítico de distribución esporotricoide76. El tratamiento de elección es anfotericina B intravenosa asociado a flucitosina oral seguido de fluconazol oral, pese al cual se describe alta letalidad por la infección67. Histoplasmosis Enfermedad causada por el hongo dimórfico geográfico Histoplasma capsulatum. Se contagia por las deposiciones de los murciélagos, clásicamente en cuevas74. En nuestro país no existe el microorganismo pero es endémico en las zonas de los trópicos77. Ocurre en 5% de los pacientes con infección por VIH que viven en áreas no endémicas y en 27% de los que viven en áreas endémicas74. El compromiso cutáneo ocurre en 11% de los pacientes por siembra hematógena, generalmente de un foco pulmonar, en los casos de histoplasmosis diseminadas74. Este compromiso pareciera ser mayor en pacientes latinoamericanos pudiendo llegar hasta 85% de los casos78. Clínicamente se presenta como máculas eritematosas, pápulas y nódulos tipo molusco contagioso67, pústulas, lesiones acneiformes, úlceras o placas vegetantes. Puede comprometer la mucosa oral en 25 a 45% de los casos79. Anfotericina B sigue siendo el fármaco de elección en los casos de histoplasmosis diseminada. Peniciliosis Enfermedad causada por el hongo dimórfico Penicillium marneffei. Es frecuente en pacientes con infección por VIH del sudeste asiático y sur de China74. La exposición laboral al suelo en la estación lluviosa de las zonas asiáticas es considerada un factor de riesgo. Puede ocurrir en forma localizada en pacientes inmunocompetentes pero en pacientes inmunosuprimidos se presenta en forma diseminada, principalmente en pacientes con recuentos de LTCD4 < 100/mm3 80. Las lesiones cutáneas ocurren en 70 a 85% de los pacientes con compromiso sistémico74,80,81. Clínicamente se observan pápulas umbilicadas tipo molusco contagioso; abscesos y nódulos subcutáneos, ubicados principalmente en la cara y el cuello81. Además pueden presentarse úlceras y pápulas con exudado amarillento, en la mucosa oral74. Coccidiomicosis, esporotricosis y aspergilosis En general las infecciones por Coccidioides immitis, Sporothrix schenkii, Aspergillus fumigatus y Aspergillus flavus se presentan como lesiones cutáneas diseminadas asintomáticas; muchas de ellas, con apariencia moluscosímil, secundarias a siembra cutánea desde un foco sistémico. Sin embargo, algunas pueden manifestarse como infecciones cutáneas diseminadas en ausencia de compromiso sistémico objetivable74,82. Aspergillus spp pueden causar enfermedad cutánea primaria por inoculación directa (bajo cinta adhesiva de catéteres venosos centrales)74. Infecciones parasitarias Las infecciones causadas por parásitos se encuentran frecuentemente en pacientes con infección por VIH. Debido a su estado inmunitario, se encuentran en mayor riesgo de contraer infecciones por Leishmania, escabiosis y existen algunos reportes de aumento del riesgo de Toxoplasma spp83. Escabiosis La infestación causada por Sarcoptes scabiei var hominis se presenta de manera atípica en este grupo de pacientes, en forma papular/nodular diseminada y en su forma hiperqueratósica (“sarna noruega”). Esta forma puede ser letal debido a sepsis de foco cutáneo por sobreinfección bacteriana. La forma noruega ocurre con mayor frecuencia cuando el recuento de LTCD4 es < 200 céls/mm3 83. Del mismo modo, puede presentarse como parte del SRI84 o simulando otras dermatosis como dermatitis de contacto generalizada, psoriasis o enfermedad de Darier83. Por esta razón, debe considerarse el diagnóstico diferencial de escabiosis en cualquier paciente seropositivo para VIH que se presente con prurito como motivo de consulta. Pese a que la escabiosis en pacientes inmunocompetentes no compromete el cuero cabelludo, los pacientes con infección por VIH/SIDA pueden tener compromiso de ese sitio anatómico83,84. En este grupo de pacientes, sobre todo los que se presentan con sarna noruega, el tratamiento con ivermectina y permetrina asociado a algún queratolítico como vaselina azufrada ha tenido buenos resultados85. Leishmaniasis Enfermedad causada por protozoos del género Leishmania. Tiene tres formas de presentación: cutánea (LC), muco-cutánea (LMC) y visceral (LV o kala-azar, del hindi “fiebre negra”). Aproximadamente dos tercios de los casos son LC o LMC y sólo un tercio corresponde a LV86. Por lo tanto, la mayoría de las infecciones por Leishmania spp. permanecen localizadas en la piel y los ganglios linfáticos loco-regionales. En general, los pacientes con infección por VIH pueden presentar formas de LC diseminadas (> 10 lesiones pleomórficas en más de dos sitios corporales no contiguos) y formas difusas (primarias cutáneas o por diseminación en forma hematógena)87. Además, tienen mayor riesgo de desarrollar compromiso de mucosas, el cual no debe ser categorizado como una LMC debido a que no tiene el período de latencia clásico88. Sin embargo, más que las formas cutáneas de leishmaniasis, la infección por VIH confiere un riesgo aumentado de 100 a veces de presentar formas de LV, lo que ha llevado a autores a proponer la inclusión de la LV como una patología definitoria de SIDA89-

Leucoplasia vellosa oral Candidiasis oral
Herpes simple tipo 1 Leucoplasia vellosa oral Candidiasis oral La leucoplasia vellosa oral fue descrita por primera vez en 1984 en pacientes jóvenes que tenían sexo con hombres seropositivos para el VIH31,32. Es el resultado de una infección causada por el virus de Epstein-Barr que lleva a un engrosamiento hiperqueratósico de los bordes laterales de la lengua, con crecimiento de las papilas, dando un aspecto corrugado o velloso de color blanquecino-grisáceo. En más del 60% de los pacientes se presenta en ambos lados de la lengua; sin embargo, el tamaño de las placas es diferente31 (Fig. 5). La lesión no se desprende al raspado. El curso clínico varía desde lesiones asintomáticas con resolución espontánea hasta exacerbaciones y lesiones sintomáticas con frecuencia coinfectadas por cándida que imposibilitan la ingesta oral31. Generalmente no requiere tratamiento, ya que resuelve con uso de terapia antirretroviral R. Garza-Garza, et al.: Manifestaciones cutáneas del VIH

Figura 17. Escabiasis costrosa
Figura 17. Escabiasis costrosa. Paciente con lesiones generalizadas de seis meses de evolución (A). De cerca, se observan placas gruesas, descamativas, de coloración verdosa-grisácea (B). Se confirmó el diagnóstico mediante examen en fresco con hidróxido de potasio (Cortesía del Servicio de Dermatología del Hospital Universitario «Dr. José Eleuterio González»). R. Garza-Garza, et al.: Manifestaciones cutáneas del VIH

HIV Dermatology in Africa Volume 18 Issue 1 February/March 2010

Volviendo al caso……

Laboratorios Carga viral (Julio/19): 190.967 copias/mL, 2,29 Log
06/09/19 Laboratorio Resultado Hb 9,5 Hto 27,8% VCM 93,1 HCM 31,7 CHCM 34,1 RDW 19 Plaquetas Leucocitos 4.120 Neutrófilos 2.200 Linfocitos 1.370 Monocitos 350 Eosinófilos 50 Basófilos 30 Laboratorio Resultado HDL 17 Bilirrubina total 1 LDL 86 AST 18 Colesterol total 123 ALT 10 Triglicéridos 163 LDH 174 Sodio 136 Ferritina 231 Cloro 96 Fosfatasa alcalina 103 Potasio 4,30 AgSHB Negativo Creatinina 0,98 HCV BUN 17,9 RPR No reactivo. Glicemia 94 Prueba treponémica Negativo. Albúmina 2,9 Carga viral (Julio/19): copias/mL, 2,29 Log LT CD4+ (Julio/19): 15/mm3

Infecciones y conteo de LT CD4+
In patients with HIV, the occurrence of specific infections is closely correlated with the degree of impairment of host defenses. The sequence of pulmonary infections occurring in HIV-infected individuals parallels the depletion of CD4 lymphocytes. As a result, the CD4 count (or the "stage" of HIV) can provide information about the type of pulmonary disease to which the patient is susceptible. The stages of HIV are defined by the CD4 count. These include early (CD4 >500 cells/microL), intermediate (CD4 200 to 500 cells/microL), advanced (CD4 100 to 200 cells/microL), and late-stage disease (CD4 <100 cells/microL). The following observations have been noted [32]: ●Sinusitis and bronchitis can occur at any CD4 count. ●Bacterial pneumonia and tuberculosis can occur early in the course of HIV infection, when the CD4 count is >500 cells/microL and before AIDS-defining opportunistic infections or neoplasms occur. However, both occur more frequently as immune function declines. ●Pneumocystis pneumonia (PCP), disseminated fungal disease, and cytomegalovirus infection almost always occur when the CD4 counts are very low, usually below 200 cells/microL. ●Human herpesvirus-8 (HHV-8)-related Kaposi's sarcoma occurs almost exclusively in HIV-infected men who have sex with men (MSM). As opposed to extensive and rapidly progressive Kaposi's sarcoma seen in the late stages of HIV infection, HHV-8 related Kaposi's sarcoma may appear extremely early in the course of HIV disease, in patients with CD4 cell counts >500 cells/microL [33]. ( The Pulmonary Complications of HIV Infection Study Group examined the incidence of pulmonary complications over five years, based upon HIV disease severity as measured by the CD4 count [32]. The following patterns were noted. ●Acute bronchitis was the most common of all respiratory infections in subjects with CD4 counts ≥200 cells/microL at study entry. ●In subjects with entry CD4 counts of 200 to 499 cells/microL, the incidence of infection caused by bacteria or PCP each increased an average of 40 percent per year. ●In subjects with entry CD4 counts <200 cells/microL, acute bronchitis and bacterial pneumonia and PCP each occurred at high rates, without discernible trends over time, despite chemoprophylaxis in more than 80 percent after one year. Pulmonary manifestations in patients with AIDS. Cristina Afione1, Alejandra Della Sala2, Laura Frank. RAR - Volumen 75 - Número

Rx de tórax

TAC de tórax PCR para MTB en Jugo gástrico negativa
Nodulillos pulmonares bilaterales, de distribución aleatoria, centrolobulillares y subpleurales, infracentimétricos. No se identifican masas o áreas de consolidación en ambos campos pulmonares. No se observa derrame pleural o pericárdico. Múltiples adenopatías en ventana aortopulmonar con tendencia a la agrupación, las de mayor tamaño en rango adenomegálico miden 12 y 10 mm en su eje menor. Adenopatías en rango no adenomegálico en cadenas axilares bilaterales. Corazón de tamaño y posición habitual. Tráquea y bronquios fuentes permeables. Esófago de diámetro y recorrido habitual. No se identifican trazos de fractura o lesiones expansivas líticas o blásticas. CONCLUSIÓN: Nodulillos pulmonares bilaterales de distribución aleatoria, a considerar proceso inflamatorio-infeccioso de tipo micótico, a correlacionar con clínica y laboratorio del paciente. PCR para MTB en Jugo gástrico negativa Bk en Jugo gástrico negativo. Bk en esputo inducido negativo.

06/09/19 06/09/19

Látex para cryptococo negativa Capa gruesa para leucocitos negativa.
Por el tipo de leisone sy cd4 y CV s esospecho cripto, histo y molusco. Látex para cryptococo negativa Capa gruesa para leucocitos negativa. Hemocultivos para hongos negativos (06/09/19) Biopsia de piel . R. Garza-Garza, et al.: Manifestaciones cutáneas del VIH. Gaceta Médica de México. 2014;150 Suppl 2:

Histoplasmosis

Introducción Hongo dimórfico Micosis endémica más común
Aumento de incidencia Mayor numero de pacientes inmunosuprimidos Tierra con guano de murciélago o deposiciones de aves Espectro clínico amplio Histoplasma capsulatum, the etiologic agent of histoplasmosis, is a dimorphic fungus highly endemic to the Mississippi and Ohio River valleys of North America. In an increasingly interconnected continent, in which millions of travelers migrate through high-prevalence areas, the Ohio River Valley fever has become a disease of international extent, much farther-reaching than the simple geographic confines of its endemicity. Moreover, with increasing numbers of patients receiving immunosuppressive therapies, including solid-organ and bone marrow transplantation and tumor-necrosis-factor inhibitors, the population at risk for histoplasmosis, including severe disseminated forms, will continue to grow. In terms of disease cadence (acute, subacute, and chronic), onset (primary or reactivation disease), distribution (pulmonary, mediastinal, disseminated, and isolated extrapulmonary) and severity (asymptomatic, mild, and moderate-severe), the clinical spectrum of histoplasmosis is very wide, often contributing to delays in diagnosis. The advent of Histoplasma antigen testing has revolutionized the diagnosis of histoplasmosis by providing a convenient and highly sensitive test; however, a multipronged approach is recommended for the diagnosis of histoplasmosis, including laboratory, radiographic, histopathologic, microbiologic, and serologic evaluation. Treatment of histoplasmosis is contingent on the severity and specific manifestation of the disease, but immunocompromised patients and disseminated disease should always be treated. Infect Dis Clin N Am 30 (2016) 207–227

Microconidas son la principal forma infecciosa
Ruta de infección: Inhalación de material aerosolizado Conidias o fragmentos de micelios Microconidas son la principal forma infecciosa Conversión dimórfica ocurre rápido Ciclo vital intracelular en macrófago alveolar Confinamiento al pulmón Diseminación vía hematógena y linfática Forma extracelular Transportado por distintos fagocitos Sitios de diseminación Hígado, bazo, MO, piel, tejido subcutáneo Infect Dis Clin N Am 30 (2016) 207–227

FR exposicionales: Trabajo en fincas
Exposición a criaderos de aves, o cuevas. Remodelación o demolición de edificios viejos Tala de árboles (nidos). Fig. 1. Geographic distribution of H capsulatum var. capsulatum (purple) and H capsulatum var. duboisii (shadow area). The circles indicate the number of published cases of autochthonous AIDS-associated histoplasmosis (via Scopus query). Themajority of African cases has been observed outside Africa. (From Bahr NC,Antinori S,Wheat LJ, et al. Histoplasmosis infectionsworldwide: thinking outside of theOhio River Valley. Curr TropMed Rep 2015;2(2):70–80;with permission.) Histoplasma may be found in so-called microfoci inside and outside the endemic areas for histoplasmosis. The characteristic of these microfoci is contamination with bird/or bat guano. The activities that have been most commonly identified as sources for exposure to Histoplasma capsulatum include farming, exposure to chicken coops or caves, remodeling or demolition of old buildings, and cutting down trees or clearing brush from sites in which blackbirds have roosted.9–11 These microfoci challenge the perception of where histoplasmosis might occur in the United States, as evidenced by recent reports from Idaho and Montana.12 Outside the United States, histoplasmosis incidence is best understood and highest in parts of Mexico and South and Central America and is largely driven by the AIDS pandemic.13–18 In French Guiana, progressive disseminated histoplasmosis (PDH) is the most common AIDS-defining illness, where this condition was detected by 1 retrospective in approximately 41% of HIV-positive hospitalized patients with fever and a CD41 count less than ,14,16,19 In Columbia, more than 70% of patients with histoplasmosis included in a survey conducted from 1992 to 2008 had HIV/ AIDS,20 and in Brazil, histoplasmosis is highly endemic in several regions; histoplasmin positivity may be up to approximately 90% in some areas.4 Histoplasmosis also is endemic in parts of Asia, Southeast Asia, and India. In China, 75% of cases occur along the Yangtze River, most in association with AIDS,21 and histoplasmin skin test positivity ranges from 6% to 50%. More than 1200 cases of PDH have been reported in Thailand22 and recent cases have been reported in South Korea as well.23 In India, cases have been recognized since the 1950s and histoplasmin sensitivity rates have been reported from 4.7% to 12.3%.24,25 Information is more limited in Africa, but cases have been reported in patients with AIDS in Zimbabwe, South Africa, Uganda, and Tanzania,9,26,27 and many cases were diagnosed in Europe after travel.25,28,29 Histoplasmosis in Europe without travel to endemic areas is rare but cases have been reported in Spain.30 The newly recognized worldwide distribution clearly has an effect on histoplasmosis management Microfocos fuera de áreas endémicas por contaminación con guano de ave o murciélago. Infect Dis Clin N Am 30 (2016) 207–227

Formas de presentación clínica
Histoplasmosis pulmonar aguda Histoplasmosis pulmonar subaguda Histoplasmosis pulmonar crónica Nódulos pulmonares Adenitis mediastinal Granuloma mediastinal Fibrosis mediastinal Histoplasmosis diseminada Pericarditis Meningitis Infect Dis Clin N Am 30 (2016) 207–227

Histoplasmosis diseminada
Diseminación hematógena durante infección aguda Rara vez reconocida clínicamente. Se recuperan con desarrollo de inmunidad celular 1 en 2000 pacientes con infección aguda Inmunosuprimidos: Riesgo 10x Disseminated Histoplasmosis Hematogenous spread outside the lungs occurs during the acute infection but is rarely recognized clinically.52 These patients recover with the development of cellular immunity to H capsulatum,52 and patients who are unable to control the dissemination are at an increased risk for developing PDH. This occurs in approximately 1 in 2000 acute infections, 17 with a 10-fold higher risk in patients who are immunosuppressed or at the extremes of age (younger children and older adults).53 If no cause for immune dysfunction is readily apparent, investigations should be undertaken to look for less apparent causes of immunocompromise,54,55 such as CD4 lymphopenia,56 common variable immunodeficiency, 54 hyper-IgE (Job) syndrome,57 and defects in the interleukin 12 or interferon gamma pathways.58 Work identifying other causes of immunocompromise is ongoing. Infect Dis Clin N Am 30 (2016) 207–227

Hepatoesplenomegalia Linfadenopatías Lesiones orales o cutáneas (6%).
Clínica Fiebre Perdida de peso Hepatoesplenomegalia Linfadenopatías Lesiones orales o cutáneas (6%). Laboratorios Anemia, leucopenia, trombocitopenia ↑ Transaminasas y bilirrubinas ↑ LDH y Ferritina Acidosis metabólica Common clinical manifestations include fever, fatigue, malaise, anorexia, weight loss, and respiratory symptoms.52 Physical examination frequently reveals lymphadenopathy, hepatomegaly, and/or splenomegaly, with skin and oral lesions less common. 59 Skin lesions seem more common in cases in Latin America.60 Laboratory tests usually show anemia, leukopenia, thrombocytopenia, and elevated hepatic enzymes and bilirubin52; elevated lactate dehydrogenase61 and ferritin62 are nonspecific but suggestive of PDH. Shock with hepatic, renal, and respiratory failure (including ARDS) and coagulopathy may complicate severe cases and may be mistaken for bacterial sepsis.63 Most common sites of involvement are liver, spleen, gastrointestinal tract, and bone marrow.13 Dissemination can also be seen in skin, adrenal glands, central nervous system, and endocardium.64 Adrenal insufficiency and reactive hemophagocytic syndrome can complicate the course.65–67 Meningitis, cerebritis, and focal brain or spinal cord lesions occur in 5% to 10% of cases, as either manifestations of widely disseminated infection or isolated findings.68 Pulmonary imaging is characterized by diffuse reticulonodular, interstitial, or miliary infiltrates but may be unrevealing in 10% to 50% of the cases Infect Dis Clin N Am 30 (2016) 207–227

Imágenes Complicaciones Infiltrados difusos Reticulonodulares Miliares
Intersticiales 10-50% no muestra hallazgos Complicaciones Shock Falla renal o hepática SDRA Insuficiencia adrenal Síndrome hemofagocitico Cerebritis, meningitis o lesiones focales de SNC (5-10%) Infect Dis Clin N Am 30 (2016) 207–227

Diagnóstico Patología Cultivo Antígeno Anticuerpos Pruebas moleculares
The diagnosis of endemic fungal infections has been standardized by the European Organization for Research and Treatment of Cancer Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group.45 Though these definitions were initially generated for research purposes, they can be of use in clinical settings, particularly with atypical presentations. A proven endemic mycosis is contingent on a compatible clinical scenario and a positive culture or histopathology. If culture or pathologic examination is not available or negative, yet the host is immunocompromised, the clinical picture is suggestive and a mycologic laboratory test is present (eg, Histoplasma antigen positivity), the diagnosis is considered probable. Si no hay cultivo o histopatología disponible  Dx probable con clínica + antígeno positivo Infect Dis Clin N Am 30 (2016) 207–227

Patología Visualizar levaduras ovoides de mm en tejido y/o fluidos. Dentro de células monofagocíticas Mejor muestra en médula y secreción respiratoria en histoplasmosis diseminada Diferentes características en tinciones: Romanowksky, Gomori, PAS, Giemsa, Mucicarmina (distingue cápsula de histoplasma de la de cryptococo). Confusión con otros hongos o microorganismos Histopatología de lesiones: Granuloma caseificante o no caseificante Demonstrating organisms on pathologic examination and/or culture is the gold standard for the diagnosis of histoplasmosis. On histopathology, the presence of caseating or noncaseating granulomas is typical but performing special stains, including Gomori methenamine silver, Giemsa, or periodic acid–Schiff stains, is usually necessary to identify yeast. H capsulatum var capsulatum yeast are between 2 to 4 mm in diameter, ovoid shaped, predominantly intracellular (within macrophages and giant cells), and characteristically divide by narrow-based budding. Cytopathologic examination of specimens obtained via fineneedle aspiration or bronchoalveolar lavage (BAL) can also demonstrate yeast cells but is less sensitive than whole tissue pathologic examination. 46 The presence of yeast forms is not pathognomonic of active disease because they may be recovered from healed granulomas or calcified lymph nodes. In these cases, the clinical picture and underlying host factors are key in distinguishing latent from active disease. H capsulatum requires 4 to 6 weeks to become detectable as a mold on fungal cultures. DNA probes may be used to confirm the presence of H capsulatum because diagnosis based on morphology alone may be challenging. Organisms can be recovered from sputum, BAL, blood, bone marrow, and biopsied tissues submitted for culture. The highest sensitivity for culture is in patients with disseminated and chronic pulmonary histoplasmosis.20 H capsulatum cultures pose a potential threat to laboratory personnel and should be handled in a biosafety level 3 laboratory. _____________________________________________________ ***** Rapid identification of H capsulatum var. capsulatum is facilitated by visualization of ovoid yeast cells measuring 2 mm to 4 mm in greatest dimension in tissue and/or body fluid specimens. The average size of H capsulatum var. duboisii (range, approximately 6–12 mm or greater), however, is often much larger than that of H capsulatum var. capsulatum, so presumptive identification should not rely solely on microscopic morphology. Budding yeast is connected at a narrow base, which helps distinguish H capsulatum from other microorganisms, including smaller forms of Blastomyces dermatitidis. Most often, H capsulatum yeast is localized within mononuclear phagocytic cells, such as macrophages and monocytes; however, in many preparations, extracellular yeast can also be observed. Additional attributes that are helpful for rendering a presumptive identification in stained microscopic preparations are its tinctorial properties and the presence of a pseudocapsule The highest yield may be achieved in respiratory specimens or bone marrow biopsy in patients with PDH.70 Less commonly, organisms may be seen in respiratory specimens, mediastinal lymph nodes, or lung tissue from patients with pulmonary histoplasmosis. Demonstration of organisms in mediastinal lymph nodes or lung tissue does not, however, distinguish active from healed histoplasmosis, because nonviable organisms persist in these tissues indefinitely. It is not uncommon to observe nonviable H capsulatum within old granulomas, a finding that can sometimes confound an inexperienced pathologist when the clinical history is inconsistent with histoplasmosis. In immunocompetent individuals, H capsulatum infection elicits granuloma formation in which yeast is often present within histiocytes. Granulomas eventually under caseation and the presence of cavitary lesions are also observable. Lesions associated with H capsulatum infection resemble those of other infectious diseases, especially tuberculosis and sarcoidosis. In cases of disseminated histoplasmosis in immunocompromised hosts, yeast forms are often found within histiocytes scattered throughout infected organs rather than in granulomas. Other fungi and microorganisms may be mistaken for H capsulatum. Fungi, including Candida glabrata, B dermatitidis, capsule-deficient strains of C neoformans and C gattii, Talaromyces marneffei, and Pneumocystis jirovecii and the protozoa Leishmania spp, Toxoplasma gondii, and Trypanosoma cruzi are common examples. Mucicarmine staining for capsular material may be used to distinguish pathogenic cryptococci from H capsulatum, but capsule-deficient strains may be misidentified by this technique. Fungal stains, such as GMS and PAS, can be used to distinguish protozoa. Table 3 shows examples and contrasts morphologic features, respectively, of microorganisms that are often confused with H capsulatum. Furthermore, H capsulatum yeast forms may be present in small numbers and are occasionally overlooked by a pathologist experienced with morphologic identification of H capsulatum. Infect Dis Clin N Am 30 (2016) 207–227

. Fig. 3 shows the microscopic
appearance of H capsulatum var. capsulatum stained by 8 different methods. Romanowsky-type stains, including Diff-Quik (Baxter [Siemens Healthcare, Malvern, PA]), Giemsa, and Wright-Giemsa stains (see Fig. 3A, B, and H), impart a dark blue hue to the fungal nuclear compartment. A thin blue rim of stained yeast sacculus and a zone of pallor near a cell pole are also readily observable. Special stains, such as the Grocott-Go¨mo¨ ri methenamine–silver (GMS), mucicarmine, and periodic acid–Schiff (PAS) stains (see Fig. 3C, F, and G), can provide contrast to yeast cells, in cases of GMS and PAS stains, but may obscure the observation of H capsulatum in the case of mucin stains, such as mucicarmine. In the latter method, however, this observations facilitates the discrimination of H capsulatum from encapsulated varieties of Cryptococcus neoformans and C gattii, which both stain red. The Gram stain can also provide useful insight into the identification of yeast within clinical specimens, including blood cultures that grow yeast forms of consistent size, shape, and budding characteristics as H capsulatum. In properly stained specimens, H capsulatum stains red or fuchsia, depending on the counterstain used. Infect Dis Clin N Am 30 (2016) 207–227

Cultivo Útil en forma diseminada y pulmonar crónica:
Positivo en 50-85% de los pacientes Sangre y medula ósea 75% de los pacientes Esputo o LBA 75% en crónica Sangre o biopsia de tejidos Se pueden requerir hasta 4-6 semanas culture media (BACTEC™, Becton Dickinson, Sabouraud’s agar) -_> toma mas de 4 ss H capsulatum because diagnosis based on morphology alone may be challenging. Organisms can be recovered from sputum, BAL, blood, bone marrow, and biopsied tissues submitted for Culture Cultures are most useful in patients with disseminated or chronic pulmonary histoplasmosis, positive in 50% to 85% of cases. In disseminated disease, the highest culture yield is from bone marrow or blood, positive in more than 75% of cases.70 Organisms can be isolated from sputum or bronchoscopy specimens from 75% of patients with chronic pulmonary histoplasmosis.70 Up to 4 weeks is required to isolate the organism in culture. The mold form of H capsulatum usually grows as a white or buff and suede-like or cottony mycelium. Microscopic examination of mold growth reveals characteristic large, rounded tuberculate macroconidia originating from short, hyaline conidiophores. Sepedonium spp produce similarappearing conidia, so definitive identification should not be based on microscopic analysis alone (see Table 3). The highly infectious microconidia may or may not be observable, however. For definitive identification, DNA probes are commonly used, but nucleic acid sequencing and other laboratory-developed molecular methods can be used. Infect Dis Clin N Am 30 (2016) 207–227

Antígeno Antígeno de galactomanano en fluidos corporales (inmunoensayo EIA cuantitativo) Mayor desempeño en diseminada y pulmonar aguda 80-95% detectado 90% en LBA en diseminada y pulmonar crónica 75% en meningitis (LCR) Histoplasmosis Sensibilidad Diseminada 91% Pulmonar crónica 87% Pulmonar aguda 83% Pulmonar subaguda 30% Antigen Testing A galactomannan antigen may be detected in the body fluids in patients with histoplasmosis, offering another method for rapid diagnosis. The highest yield for antigen detection occurs in patients with PDH or APH, in whom antigen may be detected in 80%to 95%of cases. Less often, antigen may be detected in patients with subacute or chronic pulmonary histoplasmosis.70 The highest yield for antigen detection is achieved by testing both urine and serum. For example, in APH, antigen was detected in 83% of patients by testing both urine and serum, of which more than a third were positive only in serum.71 Antigen may be found in the CSF of 75% of patients with meningitis caused by histoplasmosis (anecdotal experience of the authors) and BAL fluid in 90% of patients with chronic pulmonary histoplasmosis or diffuse pulmonary histoplasmosis, complicating PDH.72 Cross-reactions occur most often in patients with blastomycosis, penicilliosis marneffei, and paracoccidioidomycosis70; in 10% of patients with coccidioidomycosis73,74; and rarely in Aspergillosis _____________ Though culture and histopathologic diagnosis remain the gold standards for the diagnosis of histoplasmosis, antigen testing provides a reliable, noninvasive, and highly sensitive means for diagnosis. The currently available enzyme immunoassay (EIA)-based assay provides quantitative results and is highly sensitive and specific. A multicenter evaluation of this assay among 218 subjects with histoplasmosis and 229 controls revealed a sensitivity of 91.8%, 87.5%, and 83% for disseminated histoplasmosis, chronic pulmonary histoplasmosis, and acute pulmonary histoplasmosis, respectively. Sensitivity for subacute histoplasmosis was low (30%).20 A limitation of antigen testing is the significant cross-reactivity of the assay in the presence of other fungal infections, including blastomycosis, paracoccidioidomycosis, penicilliosis, aspergillosis, and coccidioidomycosis.20 Combining urine and serum antigen testing increases the overall sensitivity.47 Histoplasma antigen can also be detected in cerebrospinal fluid (CSF) and BAL fluid.48,49 This is most helpful in patients with CNS histoplasmosis and those with limited pulmonary disease, such as subacute and chronic histoplasmosis, in which serum and urine antigen might be negative. In addition to facilitating diagnosis, monitoring antigen levels is useful to follow response to therapy because antigen levels, particularly in the serum, have been shown to decline with appropriate treatment.50 Rising antigen levels can also be used as early predictors for clinical relapse or treatment failure. Infect Dis Clin N Am 30 (2016) 207–227 Azar MM, Hage CA Laboratory diagnostics for histoplasmosis. J Clin Microbiol 55:1612–1620.

Anticuerpos Marcador de infección previa o reciente  utilidad en subaguda y crónica. Toman hasta 4-8 semanas para desarrollarse, persisten por décadas Inmunodifusión Banda H  Infección activa. Banda M  Infección crónica Inmunofijación Genera títulos de ac. >1:8 en mayoría de los pacientes con contacto 1:32 ó aumento ≥ 4 veces  infección aguda Poca positividad en individuos sanos a pesar de endemicidad. Pueden negativizarse en inmunocompromiso Serology is a marker of recent or past infection and, as such, is most useful in the diagnosis of subacute or chronic disease. Anti-Histoplasma antibodies appear 4 to 8 weeks after initial infection and persist for decades. There are 3 available methods for detecting antibodies to H capsulatum: immunodiffusion (ID), complement fixation (CF), and EIA. ID detects antibodies that bind to H and M fungal antigens and subsequently precipitate on agar gel, producing bands on diffusion. The H band is found in less than 20% of patients but always indicates active infection, whereas the M band is more common (80%) but less specific for active infection.36 The CF test generates antibody titers. Acute infection is denoted by either a single titer of 1:32 or a fourfold or greater increase in antibody titers between acute and convalescent sera.51 The EIA is the most sensitive test but suffers from high false-positives and has not been standardized across laboratories, making interpretation difficult.52 A major limitation of serologic testing is in immunocompromised patients whose ability to mount a humoral immune response is reduced, such as among recipients of organ transplant who are maintained on cell cycle inhibitors.20 However, serology can be useful in patients with subacute pulmonary histoplasmosis and other populations in whom the sensitivity of antigen testing is suboptimal.53 Combining serology with antigen testing has been shown to improve the diagnostic yield for acute pulmonary histoplasmosis. ___________________ The immunodiffusion (ID), complement fixation (CF), and enzyme immunoassay are commonly used for detection of antibodies for diagnosis of histoplasmosis. H and/ or M precipitin bands are demonstrated by the ID test. H precipitins, present in less than 25% of patients, usually clear within the first 6 months after infection.76,77 M precipitins are present in 75% individuals and may persist for several years. CF titers of 1:8 or higher are found in most patients with histoplasmosis, whereas titers of 1:32 or higher are more suggestive of active infection. CF titers may persist for several years after acute infection. Both the ID and CF (ambas técnicas) should be performed to obtain the highest sensitivity for diagnosis. Cross-reactions occur in some patients with blastomycosis or coccidioidomycosis. Many physicians are unfamiliar with use these tests, believing them positive in a majority of patients from endemic areas for histoplasmosis. Positivity rates in healthy individuals who reside in highly endemic areas are low. M precipitins were present in healthy subjects in 0.5% by ID, 5% by CF, at titers of 1:8 or 1:16, and 10% by enzyme immunoassay.76,77 Antibodies require 4 to 8 weeks to develop after acute infection77 and may be negative when a patient is first seen but positive when repeated 1 to 2 months later. Antibodies also may be negative in immunocompromised patients, especially those who have undergone solid organ transplantation. Infect Dis Clin N Am 30 (2016) 207–227

In addition to its utility in diagnosis, the third-generation Histoplasma antigen EIA’s
quantitative nature allows for sequential monitoring of antigen clearance. Antigen levels, particularly in serum, have been shown to decline on effective treatment and to increase with treatment failure, providing a useful marker of treatment response. Data for monitoring of antigenemia and antigenuria have been most rigorous among HIV/AIDS patients; in this population, antigen levels in urine and serum of 2 ng/ml have been proposed as one of the requirements for cure and antifungal discontinuation (20). A limitation of Histoplasma antigen testing is the significant cross-reactivity with other fungal antigens, including Blastomyces dermatitidis, Paracoccidioides brasiliensis, T. marneffei, and less commonly, Coccidioides immitis and Coccidioides posadasii (see Table 2). False-positive reactions have also been shown to occur in 15% of transplant patients receiving anti-thymocyte globulin as part of anti-rejection treatment (21). Although low-positive results are more likely to be false positives, they are often of clinical significance and cannot be ignored. In one study of 25 patients with low-positive results and no history of histoplasmosis, 13 patients were proven to have active histoplasmosis by other diagnostic methods (histopathology, culture, serology, or PCR), and 5 patients were determined to have other fungal infections (blastomycosis or coccidioidomycosis) endemic to the area (22). Azar MM, Hage CA Laboratory diagnostics for histoplasmosis. J Clin Microbiol 55:1612–1620.

Biopsia de piel

Se tomó el 10/09/19 Cultivo de piel también positivo para histoplasma. Se envió el 06/09/19. Salió el reporte el 25/09/2019

Capa gruesa para leucocitos
Mientras espero resultado… Pancitopenia ↑ Ferritina ↑ LDH Capa gruesa para leucocitos Serum LDH levels higher than1000 IU/L are found in patients with AIDS and disseminatedhistoplasmosis. Determination of serum ferritin is also use-ful in diagnosis, since values higher than 10 g/mL in patientswith AIDS and disseminated histoplasmosis are highly spe-cific markers of this condition. Other laboratory findingsconsistent with this condition are leukopenia, lymphopenia,and monocytopenia. 4Laboratory abnormalities may also be present; pancytope-nia due to bone marrow involvement is highly prevalent.Elevated transaminase, lactate dehydrogenase (LDH), and fer-ritin are common findings. Ferritina > ng/ml es 100% específica para HD.  puede ser util para iniciar terapia empírica. Ferritina >3.000 es sugestivo de histoplasmosis

1. Se extiende  Tinción Giemsa para examen microscópico Levaduras alrededor o dentro de leucocitos. 2. Se cultiva 2.2. Buffy Coat Assay Buffy coat contains most of the white blood cells and platelets. It can be obtained after collection of four milliliters of peripheral blood in ethylenediaminetetra-acetic acid (EDTA) tube. After centrifugation of the blood sample in macrohematocrit tube in 2000 rpm for 10 min, a thin layer in between the plasma and red blood cells (the buffy coat) was transferred to a sterile glass tube. One drop of the buffy coat was placed over two glass slides and stained by Giemsa for microscopic examination. Meanwhile, another two drops were inoculated into two tubes, one containing Sabouraud Dextrose Agar (SDA) and another SDA tube with cycloheximide for agent isolation, both maintained for up to 30 days at 30 ◦C temperature. Smears for Histoplasma were considered positive when yeasts of 2–5 micrometers were identified in/or surrounding the leucocytes, and the cultures were considered as positive, if mycelium-phase as hyphae and tuberculate macroconidia were seen after staining with cotton blue. Histoplasma positive cultures are routinely sent to the Centro de Especialidades em Micologia Médica, a local reference laboratory for fungi of the Federal University of Ceará that confirms the identification by micromorphology and the conversion from the mold to the yeast phase; if necessary, the molecular method is performed Abstract: The buffy coat is obtained routinely for disseminated histoplamosis (DH) diagnosis in Ceará, Brazil. The aim of this study is to describe the accuracy of staining smears for Histoplasma in the buffy coat of AIDS-patients with DH. From 2012–2013, all results of stained buffy coat smears and culture for fungi performed at São José Hospital were recorded. In total, 489 buffy coats of 361 patients were studied; 19/361 (5.3%; 95%CI = 2.9–7.6%) had positive direct examination stained smears for Histoplasma and 61/361 (16.9%; 95%CI = 13.0–20.8%) had growth in culture. For those with positive Histoplasma cultures, the CD4 count was significantly lower (139.3 vs cells/µL; p = 0.014) than others, and death was 18%. The sensitivity and specificity of stained smears was 25.9% and 100%, respectively. A second test, performed up to 36 days from the first one, increased the sensitivity of stained smears to 32.2%. Stained smears of buffy coat have low accuracy; nonetheless, they are easy to perform and can give a quick diagnosis in low-resource endemic areas. Despite the decrease in mortality, it is not yet to the low levels observed in areas that have better and more efficient methods. J. Fungi 2019, 5, 47; doi: /jof

Medición de ferritina en 3 pacientes
4376 Pacientes con VIH 10 Pacientes con histoplasmosis diseminada The Purpose of the study was to evaluate the incidence and presentation of pulmonary histoplasmosis in AIDS patients in a non-endemic inner-city hospital in New York and compare with the presentation as reported in other nonendemic areas. METHODS This was a retrospective review of the medical records, mycology laboratory results and chest roentgenograms (CXR) of all the HIV infected patients with laboratory proven Histoplasmosis. The study period included 1993 to 1997. This study was considered exempt by the Institutional Board Review at our institution. CRITERIA FOR DIAGNOSIS Disseminated histoplasmosis was defined by the presence of extrapulmonary Histoplasma capsulatum detected by culture, peripheral blood smear, or histopathologic examination in association with an acute illness. RESULTS During the study period, 4376 HIV infected patients were admitted to our institution. Ten of these patients (0.2%) were diagnosed with pulmonary histoplasmosis. All the patients had disseminated disease. The patients we report appear to have more pulmonary manifestations and less of GI symptoms and Hepatosplenomegaly. Serum ferritin was measured in three patients and in all of them was elevated, mean value being (range 3890 to ng/ml) In contrast to the study done by Fredericks et al (5) most of our patients presented with fever, respiratory symptoms and leukopenia, and we had fewer cases with splenomegaly or lymphadenopathy. As reported by others, serum LDH and ferritin were elevated in our patients. In patients with AIDS, the combination of fever, cytopenia, elevated serum LDH level (> 1,000 IU/L), and/or hyperferritinemia (ferritin level of > 10,000 ng/mL) is a clue to the diagnosis of reactive hemophagocytic syndrome and disseminated histoplasmosis (8,9,10,11) Disseminated histoplasmosis should be considered in any AIDS patient with a low CD4 lymphocyte count, a febrile illness, an elevated ferritin and LDH levels, cytopenia, ng/ml G Diaz-Fuentes, C Shin, L Menon. Disseminated Histoplasmosis In Patients With The Human Immunodeficiency Virus (HIV) In A Nonendemic Area In New York. The Internet Journal of Infectious Diseases Volume 5 Number 2.

N= 90 casos de infecciones fúngicas endémicas
Severe pulmonary or disseminated histoplasmosis often necessitates presumptive antifungal treatment while awaiting definitive diagnosis. Histoplasma antigen assays have improved sensitivity but results may lag up to 7 days. In order to increase diagnostic certainty, “soft clues” may be looked for in laboratory and radiologic data, such as elevated alkaline phosphatase or ferritin levels and findings of mediastinal adenopathy or hepatosplenomegaly. To determine if elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio is specific to histoplasmosis or a non-specific marker for disseminated fungal infection or sepsis in general, we retrospectively examined records of all patients diagnosed with an endemic fungal infection (EFI) at Rush University Medical Center (CHICAGO) from January of 1997 to October of 2012, and a cohort of septic patients with elevated liver enzymes.We identified 90 cases of EFIs during the study period that met all inclusion criteria (Histoplasma 21, Blastomyces 56, Coccidioides 12, Paracoccidioides 1). We also evaluated 10 control patients with bacterial sepsis. Medical Mycology, 2016, Vol. 00, No. 00

reactivity of the Histoplasma antigen assay with other EFIs.
The mean ratio of AST to ALT in patients with disseminated histoplasmosis was 2.69 (95% CI:1.22, 4.16) while for other EFIs, the mean ratio ranged from 0.38 to 1.14 with disseminated coccidioidomycosis and blastomycosis respectively (P < ). The ratio in patients with bacterial sepsis was 0.84. We propose the use of the AST/ALT ratio as a clinical “soft clue” suggestive of disseminated histoplasmosis in the appropriate host, and to possibly distinguish cross reactivity of the Histoplasma antigen assay with other EFIs. ALT is produced almost exclusively in the liver, and all but the lowest elevations are associated with hepatocyte injury and cell death.5 However, even though AST is also predominantly associated with liver,6 it is produced by other cell types such as cardiac and skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes, and erythrocytes.5,6 In addition, ALT requires B6 as cofactor for its biosynthesis, while AST does not.7 The cause of this elevated ratio in disseminated histoplasmosis is unclear, but there are multiple possible causes. In alcoholism, the most common disease associated with AST/ALT ratio elevation, three possible causes have been proposed: (1) deficiency of pyridoxal 5-phosphate (the active metabolite of B6 which is required for creation of ALT, but not AST),7 (2) mitochondrial damage leading to increasedmitochondrial AST in the serum,8 and (3) decreased production of ALT from a chronically damaged liver.9 In addition, damage to organs that produce AST but not ALT, is possible in patients with disseminated histoplasmosis. This would include the reticuloendothelial system, including the spleen, muscle, intestine and kidneys. The absence of laboratory evidence of vitamin deficiency and recovery of liver function in surviving patients with histoplasmosis argue against causes 1 and 3, respectively. Ultimately, further laboratory work would be necessary to determine the cause. These results are not without important limitations. This ratio is not diagnostic but instead suggestive of disseminated histoplasmosis in the appropriate patient population. If used in settings with low pretest probability for this infection, it is likely to be limited in its value or misleading in its results. In addition, attempts to obtain CPK and LDH levels were unsuccessful, as they are not routinely collected in our hospital. Less than 5% of patients in our sample had both (data not included). Thus, we were not able to correlate this elevated ratio with other known features of disseminated histoplasmosis, such asmarkedly elevated LDH (>600) and ferritin Medical Mycology, 2016, Vol. 00, No. 00

N=1177 VIH 44 con histoplasmosis.
Introducción: la histoplasmosis es una micosis endémica en nuestro país y una complicación relativamente frecuente de los pacientes con sida. El objetivo del estudio era identificar las características clínicas, epidemiológicas y los factores de riesgo asociados a la mortalidad en pacientes con sida coinfectados con histoplasmosis. Materiales y métodos: se realizó un estudio de cohorte retrospectivo en el Hospital Universitario San Vicente de Paúl, en Medellín, con 1177 pacientes con VIH atendidos en un programa especializado de sida. Se identificaron los pacientes con histoplasmosis confirmada por aislamiento del hongo, o identificación de levaduras intracelulares compatibles con Histoplasma capsulatum, mediante microscopía. Se analizaron variables demográficas, clínicas, de laboratorio, comorbilidad, tratamiento recibido y mortalidad. Resultados: La histoplasmosis afectó a 44 de 709 pacientes con sida (6,2%). Entre éstos, el 95,4% tuvo fiebre, el 54,5% enfermedad diseminada y el 61,3% compromiso pulmonar. El cultivo fue positivo en el 89,3% y la histopatología en el 93,3%. Se encontró tuberculosis concomitante en el 15,9% y neumocistosis en el 11,4%. La mortalidad fue del 22,7%. El riesgo de morir fue mayor en pacientes con formas diseminadas (todas las muertes ocurrieron en sujetos con este tipo de compromiso), disnea (RR 13; IC95% 1,8-93,8), hipotensión (RR 4,5; IC95% 1,6-13,1), deshidrogenasa láctica (DHL) >2 veces (RR 5,2; IC95% 1,2-22,5), y fue menor en quienes recibieron Anfotericina B (RR 0,3; IC95% 0,1-0,8). Discusión: en la región, la histoplasmosis es frecuente en pacientes con sida, y el rendimiento diagnóstico de las técnicas de rutina para H. capsulatum es alto, por lo que deben solicitarse en cualquier caso compatible. Demostrar la comorbilidad sida-histoplasmosis no descarta otras infecciones oportunistas. Los pacientes con formas diseminadas, disnea, hipotensión y DHL alta tienen mayor riesgo de muerte. El tratamiento con anfotericina B se asoció con una mayor sobrevida. En nuestro estudio, las formas diseminadas de histoplasmosis, la presencia de disnea, hipotensión y niveles de deshidrogenasa láctica (DHL) mayor que dos veces el límite superior del rango normal se asociaron con más riesgo de muerte (tabla 4). Estos hallazgos coinciden con Couppié y colaboradores (22), quienes también encontraron asociación entre la presencia de disnea, los aumentos descritos de DHL y trombocitopenia < /mm3 con una mayor mortalidad, aunque esta última variable no se asoció en nuestro estudio. A su vez, Corcoran y colaboradores (27) encontraron que las formas diseminadas de histoplasmosis se relacionaban con valores de DHL >600 UI/L; Wheat11 relacionó los niveles de creatinina >2,1 mg/dL y albumina <3,5 g/dL con histoplasmosis grave, variables que no se incluyeron en nuestro análisis; Baddley y colaboradores (28) encontraron que la fungemia, creatinina ≥2 mg/dl y la edad fueron factores predictores independientes de mal pronóstico; y Pontes LB y colaboradores (29) encontraron en Brasil asociación independiente de mortalidad con hemoglobina ≤8 g/l y nitrógeno ureico ≥ 40 mg/dl. resalta el valor pronóstico de la disnea como indicador de compromiso pulmonar severo, y la utilidad de la DHL, cuyos valores elevados se asociaron independientemente a mortalidad. Estos hallazgos pueden orientar a nuestros clínicos para iniciar en forma temprana y óptima el manejo correspondiente. Infectio. 2010; 14(S2): S99-S106

Plantean tratamiento empírico si hay factores asociados a histoplasmosis severa
Enfermedad severa 28 (17%) We report factors associated with severe manifestations of histoplasmosis (such as shock, respiratory failure, and death) in patients with AIDS during an outbreak. Severe disease was present in 28 of 155 patients (17.9%). The following factors were associated with severe disease: black race (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.2–6.2); hemoglobin level !9.5 g/dL (OR, 2.7; 95% CI, 1.2–6.4), partial thromboplastin time 145 s (OR, 3.1; 95% CI, 1.1–9.3); alkaline phosphatase level >2.5 times normal (OR, 3.4; 95% CI, 1.3–8.7); aspartate aminotransferase level 12.5 times normal (OR, 4.2; 95% CI, 1.7–10.0); bilirubin level concentration 11.5 mg/dL (OR, 9.2; 95% CI, 2.5–34.3); creatinine concentration 12.1 mg/dL (OR, 8.3; 95% CI, 2.2–31.9); and albumin concentration !3.5 g/dL (OR, 4.6; 95% CI, 1.3–16.4). Zidovudine use was associated with decreased risk of severe disease (OR, 0.3; 95% CI, 0.1–0.7). Multivariate analysis showed that a creatinine value 12.1 mg/dL (OR, 9.5; 95% CI, 1.7–52) and an albumin value !3.5 g/dL (OR, 4.8; 95% CI, 1.0–22) were associated with an increased risk of severe disease, and zidovudine therapy remained associated with a decreased risk (OR, 0.2; 95% CI, 0.1–0.6). Findings associated with severe histoplasmosis should be recognized early and the cases managed aggressively. Definition of severe histoplasmosis. For this analysis, severe disease was defined as shock that required treatment with vasopressors, respiratory failure that required mechanical ventilation, or death attributed to histoplasmosis. Univariate analysis. The results of univariate analysis are summarized in table 3. The following factors were associated with increased risk of severe outcome: black race, hemoglobin level !9.4 g/dL, partial thromboplastin time 145 seconds, alkaline phosphatase level 12.5 times normal, aspartate aminotransferase concentration 12.5 times normal, bilirubin concentration 11.5 mg/dL, creatinine level 12.1 mg/dL, and albumin concentration !3.5 g/dL. Patients with nonsevere disease were more likely to have received zidovudine treatment before diagnosis of histoplasmosis than were those with severe disease (62% vs. 32%; P = .01). Factors that were not significantly different between patients with severe cases and those with nonsevere cases included sex, degree of fever, amount of weight loss, level of abnormality in leukocyte or platelet count, prothrombin time, lactic acid dehydrogenase value, creatine kinase value, and CD4 cell count. The median CD4 cell count was 20 cells/mL in the patients with severe cases (range, 6–386 cells/mL) versus 32 cells/mL in the patients with nonsevere cases (range, 2–638 cells/mL; P = .10). Furthermore, antigen concentrations were similar in the patients with severe cases and those with nonsevere cases. A similar proportion of patients in both groups had high antigen concentrations (14 units or 110 units, respectively; data not shown). Median antigen concentrations in serum were 6.2 units (range, 0.4–27.4 units) among the patients with severe cases and 3.7 units (range, 0.3–33 units) among the patients with nonsevere cases. Median antigen concentrations in urine also were similar in patients with severe and patients with nonsevere cases: 10.5 units (range, 0.4–27.4 units) and 8.7 units (range, 0.6–36 units), respectively. No statistically significant differences were observed in urine or serum antigen values between the severe and nonsevere groups. Although not significantly different, titers of complement-fixing antibodies to Histoplasma capsulatum antigen were slightly higher in patients with severe cases than in patients with nonsevere cases. Titers of antibodies to the mycelial- phase antigen above 1 : 64 were present in 27% of the patients with severe cases versus 9% of the patients with nonsevere cases (P = .08). Titers of antibodies to the yeast-phase antigen above 1 : 64 were present in 27% of the patients with severe cases versus 13% of the patients with nonsevere cases (P = .20). Multivariate analysis. The final multivariate logistic regression model included the following variables: age, race, zidovudine therapy, creatinine concentration 12.1 mg/dL, and albumin <3,5 Triazole therapy often is administered to patients who do not have manifestations of severe disease, and the mortality associated with such therapy is low (!5%) [2–4]. However, treatment with triazoles has failed for 10%–15% of patients with “nonsevere” manifestations, a circumstance emphasizing the need to identify such patients and offer them more effective Therapies Patients with factors that are known to be associated with severe histoplasmosis, including those identified by univariate analysis, should receive therapy with AmB or one of its lipid formulations and should be hospitalized to ensure prompt recognition and aggressive management of the more severe complications that portend a poor outcome, even with AmB therapy Clinical Infectious Diseases 2000;30:877–81

Considerar inicio de terapia empírica
Factores de mal pronóstico Forma diseminada Disnea Hipotensión LDH > 2 veces LSN LDH > 600 UI/L  S 50% E 89% Trombocitopenia < /mm3 Hb ≤ 8 gr/dL Creatinina > 2,1 mg/dL o BUN ≥ 40 Albúmina < 3,5 gr/dL Considerar inicio de terapia empírica En nuestro estudio, las formas diseminadas de histoplasmosis, la presencia de disnea, hipotensión y niveles de deshidrogenasa láctica (DHL) mayor que dos veces el límite superior del rango normal se asociaron con más riesgo de muerte (tabla 4). Estos hallazgos coinciden con Couppié y colaboradores (22), quienes también encontraron asociación entre la presencia de disnea, los aumentos descritos de DHL y trombocitopenia < /mm3 con una mayor mortalidad, aunque esta última variable no se asoció en nuestro estudio. A su vez, Corcoran y colaboradores (27) encontraron que las formas diseminadas de histoplasmosis se relacionaban con valores de DHL >600 UI/L; Wheat11 relacionó los niveles de creatinina >2,1 mg/dL y albumina <3,5 g/dL con histoplasmosis grave, variables que no se incluyeron en nuestro análisis; Baddley y colaboradores (28) encontraron que la fungemia, creatinina ≥2 mg/dl y la edad fueron factores predictores independientes de mal pronóstico; y Pontes LB y colaboradores (29) encontraron en Brasil asociación independiente de mortalidad con hemoglobina ≤8 g/l y nitrógeno ureico ≥ 40 mg/dl. resalta el valor pronóstico de la disnea como indicador de compromiso pulmonar severo, y la utilidad de la DHL, cuyos valores elevados se asociaron independientemente a mortalidad. Estos hallazgos pueden orientar a nuestros clínicos para iniciar en forma temprana y óptima el manejo correspondiente. Infectio. 2010; 14(S2): S99-S106

Tratamiento Suele ser autolimitada en pacientes sanos
Indicación en contacto reciente Inmunosuprimidos suelen diseminar Indicación en todos Tratamiento en VIH Infect Dis Clin N Am 30 (2016) 207–227

Diseminada progresiva
Tratamiento especifico y de inmunosupresión Anfotericina B por 2 semanas Respuesta- Liposomal 88% vs 64% Deoxicolato Mortalidad- Liposomal 2% vs 13% Deoxicolato Itraconazol por 12 meses Fluconazol, Voriconazol, Posaconazol Negativización de antigenemia y antigenuria A multicenter, randomized, blinded clinical trial demonstrated a higher response rate (88% vs. 64%) and lower mortality rate (2% vs. 13%) in patients who had AIDS and progressive disseminated histoplasmosis and who were treated with liposomal amphotericin B than among recipients of amphotericin B deoxycholate, respectively [8]. Amphotericin B lipid complex has also been used successfully for treatment of histoplasmosis [9] and may be preferred by some because of lower cost. Amphotericin B deoxycholate is the least expensive formulation and is a reasonable alternative to the lipid formulations for patients who are at a low risk for nephrotoxicity. Presently, except for children, for whom a 1-month course of amphotericin B deoxycholate is usually curative, it is rare to see amphotericin B given for the entire course of therapy, as was recommended in the 2000 guidelines. However, amphotericin B, as sole therapy, is effective and may be preferred in situations precluding treatment with itraconazole or other oral azoles. Generally, amphotericin B is used initially until the patient has shown a favorable response and can take an oral antifungal agent; then, itraconazole is given for the remainder of the treatment course. Itraconazole given orally is preferred for patients who have mild-to-moderate histoplasmosis and, as noted above, as stepdown therapy after the initial response to amphotericin B. The response rate for primary therapy with itraconazole in early studies was 100% for disseminated histoplasmosis and 80% for pulmonary histoplasmosis [10]. The oral capsule formulation or the solution can be used. Itraconazole capsules should be taken in the setting of high gastric acidity (concomitant consumption of food or a cola drink is recommended), to maximize absorption. In patients who are receiving antacids, H2 blockers, or proton pump inhibitors, the capsules should not be used because of decreased absorption. Itraconazole concentrations are higher with use of the solution given on an empty stomach than with capsules; thus, the solution should be used whenever possible. However, some patients dislike its taste or experience unacceptable gastrointestinal side effects, reducing adherence to therapy. Some patients are intolerant of itraconazole, are unable to achieve adequate blood levels with either preparation, or are receiving concomitant medications that lead to serious drug interactions with itraconazole. Thus, there is a need for alternative therapies. Fluconazole has been used successfully for treatment of histoplasmosis, but it appears to be less effective than itraconazole. In patients with disseminated histoplasmosis who did not have AIDS, fluconazole (200–800 mg daily) was effective in 70% of cases [15]. Fluconazole (800 mg daily for 12 weeks as induction therapy, followed by 400 mg daily) [16] was less effective than itraconazole [11] for treatment of histoplasmosis in patients who had AIDS, and fluconazole resistance developed in patients who failed therapy [17]. Ketoconazole is seldom used for histoplasmosis in the United States because of the increased number of adverse effects, compared with itraconazole. However, it is effective and much less expensive than itraconazole, justifying its use in some cases involving mild manifestations of histoplasmosis, but not in cases of disseminated or CNS disease. The newer azoles, posaconazole and voriconazole, also demonstrate in vitro activity against H. capsulatum [18]. Posaconazole appears to be more active in vitro [18] and in experimental infection [19]. Isolates that were noted to have become resistant to fluconazole when patients with AIDS were treated with the agent were also noted to show increased MICs to voriconazole [18], suggesting that resistance may develop during treatment with voriconazole, as well as with fluconazole [17]. Both voriconazole [20–24] and posaconazole [25–27] have been used successfully in a small number of patients with a variety of different forms of histoplasmosis. Data are inadequate to make an evidence-based recommendation, and all 4 of the other available azoles (i.e., fluconazole, ketoconazole, voriconazole, and posaconazole) are second-line alternatives to itraconazole. The azoles exert their antifungal activity by inhibition of the fungal cytochrome P450 3A4-dependent enzyme lanosterol 14- a-demethylase. The azoles vary in their ability to inhibit mammalian cytochrome P450 metabolism of other drugs, and several azoles (itraconazole and voriconazole) are extensively metabolized by hepatic cytochrome P450 enzymes. Thus, drugdrug interactions mediated through cytochrome P450 pathways are common and vary with each azole. In addition, posaconazole and itraconazole are both inhibitors and substrates of p-glycoprotein, and posaconazole is eliminated through glucuronidation, leading to other important drug-drug interactions. Up-to-date prescribing information should be reviewed before initiating azole therapy in patients who are taking other medications. The azoles may be hepatotoxic. Hepatic enzyme levels should be measured before therapy is started and at least at 1, 2, and 4 weeks and then every 3 months during therapy. Infect Dis Clin N Am 30 (2016) 207–227

Dx VIH Lesiones en piel CV 90.967 copias/mL (4,96 Log) LT CD4+ 15/mm3
Inicio de TARV CV 196 copias/mL (2,29 Log) LTCD4+ 86/mm3 20 días Julio 2019 Agosto 2019 Septiembre 2019 Octubre 2019 Carga viral LT CD4+ CV copias/mL (23/07/19) CD4+ 15 (22/07/19 CD4+ de 15 (22/07/2019) Carga viral (10/09/19): 196 copias/mL, 2,29 Log LT CD4+ (02/10/19): 86/mm3

Síndrome de reconstitución inmunológica (IRIS)

Generalidades Desórdenes inflamatorios asociados a un empeoramiento paradójico de procesos infecciosos pre-existentes luego del inicio de TARV. Infecciones diagnosticada previamente o latente. R/ autolimitada especialmente si se trató la infección. IRIS temprano <3 meses IRIS tardío: 3-12 meses de iniciada TARV. INTRODUCTION IRIS can be defined as a worsening of a patient’s clinical condition after initiating cART that is attributable to the recovery of the immune response to viable or nonviable pathogens. The The term "immune reconstitution inflammatory syndrome" (IRIS) describes a collection of inflammatory disorders associated with paradoxical worsening of preexisting infectious processes following the initiation of antiretroviral therapy (ART) in HIV-infected individuals [1-6]. Preexisting infections in individuals with IRIS may have been previously diagnosed and treated or they may be subclinical and unmasked by the host's regained capacity to mount an inflammatory response [7]. If immune function improves rapidly following the commencement of ART, systemic or local inflammatory reactions may occur at the site or sites of the preexisting infection. This inflammatory reaction is usually self-limited, especially if the preexisting infection is effectively treated. However, long-term sequelae and fatal outcomes may rarely occur, particularly when neurologic structures are involved. This topic focuses on the immunobiology, pathogenesis, and clinical features of IRIS. Topic reviews that discuss when to initiate ART are presented separately. Paradoxical inflammatory syndromes similar to those seen in HIV-infected patients have also been described in HIV-uninfected patients following treatment for tuberculosis [10-13] or lepromatous leprosy [14]. Similar illnesses have also occurred in some HIV-uninfected patients following corticosteroid withdrawal, discontinuation of antitumor necrosis factor alpha therapy, recovery of neutropenia after cytotoxic chemotherapy, withdrawal of immunosuppression in transplant recipients infected with Cryptococcus neoformans, and engraftment of stem cell transplantation J. Fungi 2018, 4, 139; doi: /jof

IRIS de desenmascaramiento
IRIS paradójico Infección conocida Infección diagnosticada y tratada primariamente con aumento de R/ inflamatoria secundaria durante tto antimicrobiano y TARV IRIS de desenmascaramiento Infección no conocida Sx de enfermedad que recién aparecen luego de recuperación inmunológica. R/ inflamatoria excesiva a IO subclínica o no diagnosticada IRIS is commonly divided into two clinical pictures. “Paradoxical” IRIS refers to a primarily diagnosed and treated infectious disease with a secondary inflammatory increase occurring during antimicrobial treatment and immunodeficiency reversal [6]. “Unmasking” IRIS refers to disease symptoms that first appear after immune recovery [6]. First, it may occur in relation to the unmasking of a previously untreated OI soon after HAART is commenced. In this scenario the patient has an infection that is unrecognized by the clinician when HAART is initiated, but days to weeks after initiation of HAART the infection is unmasked and may manifest with an atypical presentation, as described previously. The inflammatory reaction is targeted at replicating microbial antigen. Second, IRIS may manifest as a paradoxical reaction in a patient receiving appropriate antimicrobial therapy. In this scenario, an OI is diagnosed before HAART commencement, and there is clinical improvement during antimicrobial therapy. When HAART is initiated, the patient presents with worsening or new symptoms, signs, or radiologic manifestations of the infection. This presentation does not reflect treatment failure but rather an inflammatory reaction targeted at dead or dying microbial antigen. This reaction is best described for TB and cryptococcal meningitis [5,16–19]. Third, IRIS may manifest as an autoimmune condition such as Grave’s disease [20]. The target of the inflammatory reaction in this case is host antigen. IRIS reactions targeted at inert foreign antigens such as tattoo pigment have been described [21]. In cases of unmasking IRIS, the OI needs to be diagnosed and treated appropriately with antimicrobials. HAART should be continued. In paradoxical reactions, it is first important to consider differential diagnoses, including antimicrobial resistance, a drug reaction, or another untreated infection. Management of these patients involves continuing HAART and OI treatment, symptomatic therapy, and consideration of corticosteroids in severe cases. Consideration should be given to stopping HAART in life-threatening cases [42]. J. Fungi 2018, 4, 139; doi: /jof

Incidencia IRIS 30% de pacientes que responden a TARV desarrollan IRIS. Menor incidencia si se inicia antes de decline de CD4+. Incidencia varía según últimas series: 7,6-13% Mortalidad 3-20% Early retrospective case series studies suggested that up to 30 percent of patients who responded to antiretroviral therapy (ART) developed one or more inflammatory syndromes consistent with an immune reconstitution inflammatory syndrome (IRIS) [2,27]. However, subsequent data have suggested that the incidence is probably much lower, particularly in patients where ART was initiated before severe CD4 decline occurs. Data from prospective and retrospective studies suggest that the incidence of IRIS following ART is largely dependent on two things: 1) the likelihood of a preexisting opportunistic infection and 2) the likelihood of a viral and immunologic response to ART. The following studies illustrate the incidence of cases that have been reported in a variety of settings and the range of infections that have been described: ●In a systematic review and meta-analysis of about 13,000 HIV patients, 13 percent of subjects developed IRIS [34]. Some of the most common diagnoses included tuberculosis, herpes infections, cryptococcal meningitis, CMV retinitis, and PML. ●In a prospective trial that evaluated the optimum management of patients with AIDS-related opportunistic infections (A5164), the incidence of IRIS was 7.6 percent, which occurred a median of 33 days after the initiation of ART [26]. ●In another prospective cohort study in South Africa, an overall incidence rate of 25 cases of IRIS per 100 patient-years was reported, affecting approximately 10 percent of subjects [31]. Clinical Infectious Diseases 2009; 48:101–7

Factores de riesgo ↑CV y ↓ CD4+ (<200/mm3) al inicio de TARV
Grado de recuperación inmune con TARV Grado de decline de CV Infecciones oportunistas Infecciones fúngicas (excepto pneumocystosis) Fugura: Metaregression analysis of 21 studies for the relation of median CD4 cell count at the start of ART with the incidence of IRIS showed an exponential increase in occurrence as the CD4 cell count declined, which seemed to be independent of previously diagnosed opportunistic illness (fi gure 3). In univariable analysis the coeffi cient associated with log median CD4-cell count was –0・61 (95% CI –1・18 to –0・04, p=0・04). The coeffi cient changed little when adjusting for opportunistic illnesses: –0・80 (95% CI –1・74 to 0・13, p=0・09). Webappendix p 7 gives details. In analyses stratifi ed by median CD4 cell count at the start of ART, IRIS developed in 20・7% (95% CrI 9・0–45・7) of patients with tuberculosis in studies with a median CD4 cell count of fewer than 50 cells per μL (four studies), and in 17・7% (5・4–54・2) of patients in studies with more 50 cells per μL (four studies). IRIS was recorded in 28・3% (6・1–68・2) of patients with cryptococcal meningitis in studies with fewer than 50 cells per μL (two studies) and 2・0% (0・2–15・5) of those in one study with more than 50 cells per μL. In patients with cytomegalovirus retinitis, IRIS developed in 37・7% (16・8–61・7%) of those in studies with fewer than 50 cells per μL (four studies); no studies had more than 50 cells per μL. For patients with any type of IRIS, CD4 cell count was reported in six studies; all studies had median CD4 cell counts of more than 50 cells per μL, and 17・7% (10・5–27・7) of patients developed IRIS. ________________- The most recognized risk factors for the development of paradoxical IRIS are a very low CD4+ T-cell count (<100 or <50, depending on the study, or a percentage lower than 10%), disseminated infection with(out) a high count of the causative pathogen and earlier initiation of cART after starting antimicrobial treatment [16–19]. In a multivariate analysis, the use of potent antiretroviral drugs, such as ritonavir-boosted protease inhibitors, was also associated with IRIS [20]. The multivariate analysis of the ACTG A5164 study [21] revealed the incidence of IRIS to be associated with a lower baseline CD4+ T-cell count, higher CD4+ T-cell count during cART, baseline HIV RNA levels, HIV RNA levels during cART and the presence of a baseline fungal OI not associated with Pneumocystis jiroveci pneumonia. FR: ♂ Alta carga viral LTCD4+ < 200 OI (no conocidas o en tto actual) Several studies have demonstrated that lower CD4 cell counts or high HIV RNA at the time of treatment initiation increase the risk of developing an immune reconstitution inflammatory syndrome (IRIS) [2,26-28,31,47]. Response to antiretroviral therapy (ART) also plays an important role in predicting risk. In one prospective trial of 282 patients with AIDS-related OIs, the risk of IRIS was related to low CD4 counts at baseline (HR = 0.79 per 10 additional CD4 cells/microL; 95% CI 0.65, 0.97) and degree of immunologic improvement on ART (HR = 1.08 per additional 10 CD4 cells/microL; 95% CI 1.03, 1.13) [26]. Similarly, the risk of IRIS was also associated with a higher level of viremia at baseline (HR = 2.5 per 1 log increase in HIV RNA; 95% CI 1.19, 5.21) and the degree of viral decline on ART (HR = 0.43 per 1 log increase in HIV RNA; 95% CI 0.24, 0.78). Fungal infections (except for Pneumocystis) were also associated with an increased risk of IRIS in the multivariate analysis. Clinical Infectious Diseases 2009; 48:101–7 Lancet Infect Dis 2010; 10: 251–61

Inmunopatogénesis Figure 1. Classical model of immunopathogenesis of IRIS. Before initiation of combined antiretroviral treatment (cART), immune control of microbial replication may be poor and immune activation by expansion of pathogen-specific activated effector T cells may be intense. Two general populations coexist in this phase, namely, the nonfunctional HIV-infected T-cell (predominantly RO-nonactive [1]) and the non-HIV-infected population. After initiation of cART, HIV-RNA plasma levels fall (red line) and CD4+ T-cell rise (green line); in a first phase, memory + T cells from the lymph nodes are redistributed to the periphery (2); in a second phase, naı¨ve CD4+ T-cell count increases (3) and a shift in the T-cell receptor repertoire from Th2 to Th1 is observed (4) [48]. Previously inactive CD4+ T cells become functional (5). In this context, a high antigen concentration produces hyperactivation of the immune system, and proinflammatory cytokines and chemokines are released (6). Release of IL-2 at high concentration promotes activation-induced cell death [60] (7). Innate immunity cells such as macrophages (MF) and dendritic cells (DC) may play a role by presenting viable or nonviable antigens (8). Treg have been reported for quantitative [61] and more often for qualitative defects (e.g., higher frequencies of Treg expressing programmed death- 1 [62]) (9). In IRIS associated with bacteria and fungi, the CD4+ Th1 pathway predominates (10), whereas virus-associated IRIS probably involves a CD8+ T-cell-specific response (CTL, cytotoxic T lymphocytes [11]). This IRIS model was based on Kestens et al. [49] and Bonham et al. [54]. __________________________________________________________---- Immunopathogenesis of IRIS Despite abundant data on IRIS, pathogenesis remains speculative. IRIS is probably not a single syndrome and its pathogenesis could vary depending on the pathogen implicated (bacteria, fungi or parasites on the one hand and viruses on the other hand) and the type of IRIS (paradoxical vs unmasking). The ‘classical’ model of pathogenesis of IRIS involves basically three factors: antigen load; degree of pathogen-specific immune response recovery after the start of HAART; and host genetic susceptibility. . The presence of high levels of both viable or nonviable microorganisms could be the antigenic trigger for IRIS. Recent data on cryptococcal IRIS suggest that a persistent CSF-positive culture before starting HAART is a strong predictor of IRIS [30]. Patients with higher titers of serum cryptococcal antigen are also prone to develop IRIS [13]. In the context of tuberculous meningitis IRIS, a positive CSF culture before starting HAART for mycobacteria also significantly increases the risk for IRIS [41]. Another cornerstone of classical theory of IRIS is the pathogenspecific immune reconstitution. In general terms, soon after initiation of cART, restoration of the CD4+ T-cell count occurs in two phases [42,43]. The initial phase is characterized by a redistribution of activated memory T cells [44], diminished cell apoptosis [45] and improved thymopoiesis [46]. The rapid restoration of immune memory at this stage may play a role in recognizing previous antigenic stimuli and thus enhance IRIS. The second phase begins 4–6 weeks later (probably longer in patients with advanced disease [47]), comprises an increase in the naı¨ve CD4+ T-cell count and a shift in the T-cell receptor repertoire from Th2 to Th1 [48]. The effector cells involved in IRIS may be analogous to the effector cells in the normal immune response to specific pathogens, although in IRIS, the response is paradoxically exaggerated [49]. Antigens of viable or nonviable pathogens may activate dendritic cells and macrophages, which in turn activate Th1 memory cells, thus promoting their differentiation into CD4+ Th1+ effector cells [50–53]. The proliferation of effector CD4+ and CD8+ cells and cytokine pathway activation could be suppressed by Treg (9), thus limiting the immune response to microbial antigens. Naıve helper T cells (Th0) differentiate into Treg via signaling by TGF-b, IL-7 and IL-10 [54]. The maintenance of homeostasis is made possible by the anti-inflammatory activity of Treg. IL-6 has a critical role in this balance, and some studies have already demonstrated increased serum levels of IL-6 in association with IRIS (6) This cytokine preferentially induces Th17; in its absence, Treg differentiation can occur. Th17 is a key element in the maintenance of the inflammatory response [55]. A reciprocal relationship exists between proinflammatory Th17 and antiinflammatory Treg. IRIS could be the consequence of unbalanced reconstitution of overactivated T cells and Treg [43,49,56,57]. As stated above, the pathogenic pathways triggering IRIS seem to be slightly different for bacteria and fungi on one hand and viruses on the other hand [10]. For example, mycobacterial and cryptococcal IRIS have been associated with overproduction of CD4+ Th1-mediated cytokines, such as IFN-g [58]. In virusassociated IRIS, the mechanism is probably CD8-mediated: JC polyomavirus-associated IRIS is probably correlated with a specific CD8+ T-cell response in the CNS [59]. The pathogenesis of IRIS may also differ for the same pathogen depending on the clinical manifestation, and paradoxical and unmasking IRIS may have different pathogeneses. Haddow et al. [63] reported that, while serum C-reactive protein levels are typically elevated in all forms of IRIS, levels of MCP-1 and IL-10 are reduced in paradoxical TB-associated IRIS, whereas cases of TB-associated unmasking IRIS have higher pre-ART levels of IFN-g, as well as higher levels of TNF-a, at the time of the event. In contrast with this view involving pathogen-specific immunity, in more recent years, the innate immune system has acquired increasing interest in explaining the pathogenesis of IRIS [41,64]. Granulomatous and suppurative forms of TB-IRIS may involve macrophages [65] and neutrophils [66], respectively. Metalloproteinase secreted by epithelial cells upregulated by pro-inflammatory cytokines has also recently been implicated in tissue damage in TB-IRIS [67]. Some studies have also implicated NK cells in the pathogenesis of IRIS. Conradie et al. [68] concluded that NK cell activation in combination with lymphocyte count was the hallmark of the immunological profile of patients with unmasking TB-IRIS, compared with HIVinfected individuals with and without TB. . However, as only one in four patients experiences symptomatic IRIS, genetic characteristics, such as carriage of specific HLA haplotypes, may explain why patients with similar clinical conditions develop IRIS or not. For example, Price et al. postulated a potential association between herpes virusassociated IRIS and carriage of HLA-B44, HLA-A2, HLAB44 and HLA-DR [69]. A better knowledge of the pathogenesis of IRIS could provide clinicians with more reliable biomarkers to identify patients at risk for developing paradoxical or unmasking IRIS and could prove useful in distinguishing IRIS from other clinical conditions [7]. Some studies have already demonstrated increased serum levels of IFN-g, IL-6 and TNF-a in patients with IRIS [70,71]. However, in these studies, the control group was asymptomatic patients and not individuals with drug reactions or with active infections; for this reason, the prediction of these markers in IRIS should be subjected to further studies. Other studies have demonstrated that patients developing TB-IRIS or ART-associated TB exhibit higher CXCL10 (also known as INF-g-induced protein 10) responses to region of difference 1 antigens of Mycobacterium tuberculosis compared with controls before starting HAART [72]. The authors suggest that the assessment of T-cell responses to region of difference 1 antigens by assaying CXCL10 in whole-blood assays could perform as well as IFN-g and may have clinical utility in the detection of subclinical M. tuberculosis infection, and prediction and diagnosis of TB-IRIS and ART-associated TB. Further studies are warranted to elucidate the pathogenesis of this complex clinical syndrome Expert Rev. Anti Infect. Ther. 13(6), (2015)

Criterios diagnósticos
¿Nuestro paciente? French et al (2004):10 any cases • Diagnosis requires both major criteria or one major criterion plus two minor criteria Expert Rev. Anti Infect. Ther. 13(6), (2015)

Diagnóstico diferencial
Progresión de IO iniciales por resistencia microbiana o no adherencia a tto. Desarrollo de IO nueva Toxicidad por drogas Reacción de hipersensibilidad abacavir (HLA-B*57:01.) The differential diagnosis of an immune reconstitution inflammatory syndrome is broad and includes progression of the initial opportunistic infection (OI) due to antimicrobial resistance or nonadherence to prescribed drug regimens, development of a new OI, or drug toxicity. Although the hypersensitivity reaction seen with abacavir may be difficult to distinguish from systemic IRIS, this complication of abacavir is exceedingly rare in individuals negative for HLA-B*57:01. Prevention, diagnosis, and management of abacavir hypersensitivity is discussed elsewhere. (See "Abacavir hypersensitivity reaction".) Lancet Infect Dis 2007; 7: 395–401

Microorganismos Figure 2: Incidence of immune reconstitution infl ammatory syndrome (IRIS) in patients starting antiretroviral therapy for HIV infection, by type of study population CrI=credibility interval. NA=not applicable Lancet Infect Dis 2010; 10: 251–61

IRIS - Histoplasmosis Efecto de los antifúngicos en el desarrollo del síndrome de reconstitución inmune Por otro lado, se ha descrito que los antimicóticos más comúnmente utilizados para tratar las infecciones fúngicas invasoras presentan propiedades inmunomoduladoras, entre ellas las proinflamatorias. Antifúngicos como la anfotericina B, los triazoles (entre ellos, el fluconazol y el voriconazol) y las equinocandinas parecen tener un efecto inmunomodulador, aumentando la actividad de las células fagocíticas (monocitos, macrófagos y neutrófilos), lo que podría a su vez, contribuir de forma indirecta a la respuesta proinflamatoria exagerada observada en ciertos pacientes con IRIS bajo tratamiento antifúngico27,36

Generalidades Síntomas constitucionales 1-4 meses pos TARV
Sx focales por inflamación de lesiones preexistentes Granulomas hepáticos Uveítis Artritis Adenopatías necróticas Obstrucción intestinal por colitis granulomatosa Infarto esplénico Síndrome hemofagocítico Lesiones en piel Meningitis aséptica. Histoplasmosis Existe menos información sobre fenómenos de reconstitución inmune en pacientes con histoplasmosis y VIH que para la criptococosis. En un estudio que evaluó los casos de histoplasmosis en una zona no endémica, reportan una prevalencia del 11%50. El IRIS en pacientes con histoplasmosis se manifiesta con síntomas constitucionales en la mayoría de los casos 1-4 meses después del inicio de la ART50,51. En estos pacientes, además de los síntomas focales asociados a la inflamación de lesiones preexistentes, puede haber compromiso de otros órganos diferentes a los del compromiso inicial (como granulomas hepáticos, uveítis, y artritis)52. Específicamente asociado al IRIS por Histoplasma se ha reportado la aparición de adenopatías necróticas, obstrucción intestinal secundaria a colitis granulomatosa, infarto esplénico, síndrome hemofagocítico, lesiones en piel y meningitis aséptica50,51. Histológicamente, las lesiones corresponden a granulomas con células gigantes y necrosis, los cuales clásicamente se observan en pacientes inmunocompetentes y no en inmunocomprometidos. No obstante, la evolución de estos pacientes es favorable a pesar de continuar con la ART. En un reporte de caso de un paciente que debutó con un cuadro de histoplasmosis diseminada y hemofagocitosis 3 semanas después de iniciar la ART con evidencia de respuesta inmunológica y virológica, el desenlace fue favorable con el tratamiento para la histoplasmosis, y el síndrome hemofagocítico mejoró sin necesidad de adicionar esteroides ni suspender la ART53. Infectio. 2012;16(Supl 3): 51-58

2017 Abstract Histoplasmosis is an uncommon cause of hepatosplenomegaly in South Africa. A case of immune reconstitution syndrome (IRS) to disseminated histoplasmosis in a patient Case Report A 32-year-old male with fever, left flank pain, hepatosplenomegaly, and bicytopenia was referred from a local hospital to a tertiary hospital in Kwazulu-Natal, South Africa. The patient experienced an increase in abdominal circumference over 3 months. He had a 6-month history of gradual weight loss of approximately 10 kg with intermittent fever and rigors. He tested positive for HIV infection (CD4 count 20 cells/mm3) at his local hospital and was in the process of being prepared for the initiation of highly active antiretroviral therapy (HAART). On examination, the patient was febrile (39.8C). He was pale and had generalized lymphadenopathy (<0.5 cm in diameter). He had splenomegaly that extended 10 cm below the costal margin and a liver span of 16 cm. The full blood count showed a hemoglobin 6.6 g/dL (normochromic, normocytic anemia), platelets /L, and white cell count /L. Liver function tests revealed a hyperglobulinemia. He had an erythrocyte sedimentation rate (ESR) of 113 mm/h, and his urea and electrolytes were normal. Hepatitis screens were negative. The malaria smear was negative. The chest radiograph was normal. Ultrasound of the abdomen revealed abdominal lymphadenopathy in addition to hepatosplenomegaly. A bone marrow aspirate and trephine was done in the first instance to investigate the bicytopenia. The bone marrow aspirate and trephine showed granuloma and characteristics of histoplasmosis. Tuberculosis was excluded by the absence of acid fast bacilli on bone marrow and trephine and liver biopsy. The patient was treated with intravenous amphotericin B (1 mg/kg per d) for 14 days followed by itraconazole 200 mg twice daily. Renal impairment, hypokalemia, and thrombophlebitis complicated his therapy with amphotericin B. After 7 days of itraconazole, he was commenced on HAART: lamivudine (3TC), stavudine (d4T), and efavirenz (EFV). On day 30 post commencement of HAART, he developed pyrexia and left upper quadrant pain. The spleen size had increased, and the actual size was unfortunately not documented. An ultrasound of the abdomen revealed an enlarged spleen with a splenic abscess and features suggesting impending splenic abscess rupture. He had a laporotomy with splenectomy and a wedge liver biopsy. The liver biopsy revealed histoplasmosis by eosin and hematoxylin staining. The splenic tissue histology could not be retrieved. The viral load at this admission was <400 copies/mL. The patient was recommenced on intravenous amphotericin B. This resulted in defervesce. After 10 days of amphotericin B, he was recommenced on itraconazole 200 mg twice daily presented to a tertiary hospital in Kwazulu-Natal, South Africa, is described. _____________________________________ 2017 Patient presentation: A 39-year-old man presented with a three month history of asymptomatic papules and nodules with necrotic centres involving the centrofacial region. The patient was diagnosed as being HIV-positive a month earlier and was commenced on antiretroviral treatment. Two weeks after the development of skin lesions, the patient complained of a sore throat and hoarseness of his voice. A fibre-optic laryngoscopy and biopsies of the skin, larynx and liver were performed. Management and outcome: The CD4 counts increased from 2 cells/μL to 124 cells/μL, whereas the viral load decreased from one million to less than 20 copies/mL. A fibre-optic laryngoscopy revealed a supraglottitis with ulceration on the epiglottis. Histology of the liver, larynx and sections of the skin demonstrated pandermal necrotising granulomatous inflammation. Grocott-Gomori methenamine silver and Periodic acid–Schiff (PAS) stains revealed a relative paucity of intracellular, narrow-neck budding fungal organisms. Culture findings confirmed the diagnosis of histoplasmosis. The patient was treated with intravenous amphotericin B for two weeks followed by oral itraconazole 100 mg twice a day, with an excellent response to treatment. ______________________________________________________- Abstract: A 27-year-old HIV-positive male patient with disseminated cutaneous histoplasmosis was treated with both HAART and amphotericin B (total accumulated dose of 0.5g). Amphotericin B was later replaced with itraconazole (200mg/day). Two months after therapy had been started and the cutaneous lesions had healed, the patient interrupted both treatments voluntarily and his health deteriorated. HAART was then re-introduced and CD4+ cell count increased sharply at the same time as lymph node histoplasmosis was diagnosed. This paradoxical response ? the relapse of histoplasmosis and concomitant increase in CD4+ cell count and undetectable viral load after resumption of HAART ? suggests that this was a case of immune reconstitution inflammatory syndrome (IRIS). Journal of the International Association of Physicians in AIDS Care 10(5) S Afr J HIV Med. 2017;18(1), a org/ /sajhivmed. v18i1.693 An Bras Dermatol. 2011;86(4Supl1):S

Figure 1 presents baseline radiological findings (a–b),
skin lesion with histology (c–d) and cultural examinations showing Histoplasma capsulatum (e–f). A 32-year-old HIV-infected male from Ecuador with a history of pulmonary tuberculosis (TB) incompletely treated in 2002 was referred to our hospital in 2010 due to fever, cough, weakness, weight loss, and sore throat. Chest x-ray showed a miliary TB-like involvement and combination therapy with rifampicin, isoniazid, ethambutol, and pyrazinamide was started. Diagnostic tests for active TB (acidfast bacilli smear, Gen-Probe and cultures) were negative on sputum, bronchoalveolar lavage, blood, urine, and feces. The interferon gamma release assay and tuberculin skin test were also negative. The patient was severely immunocompromised, with a lymphocyte CD4+ cell count of 35/mmc (8%) and plasma HIV-RNA of 46,600 copies/ml. Combined antiretroviral treatment (cART) with tenofovir/emtricitabine plus lopinavir/ ritonavir was subsequently started after 2 weeks of antitubercular therapy. Rifampicin was replaced with linezolid due to known drug interactions. Despite this, the patient’s clinical condition did not improve after 2 weeks on cART. He developed acute respiratory insufficiency with high oxygen supplementation and infiltrative necrotic papular lesions appeared on his face, throat, neck, and scalp. A skin biopsy and fine-needle aspiration for culture were conducted. Grocott’s methenamine silver stain showed a fungal infection and amphotericin B lipid complex (ABLC) 5mg/kg daily was started. Serological tests for Histoplasma capsulatum and Coccidioides immitis, plasmatic and liquoral cryptococcal antigen were negative, but tests for serum (1–3)-b-d-glucan and galactomannan were positive ( > 523 pg/ml and 0.69 OD index with a cut-off of 80 pg/ml and 0.5 OD index, respectively). Therefore a videothoracoscopic lung biopsy was performed demonstrating mycotic granulomatous pneumonia and antitubercular therapy was stopped. Hyphal colonies appeared after 3 weeks of culture on Sabouroud dextrose agar and complete identification of Histoplasma capsulatum var. capsulatum was confirmed with conversion of the mold to the yeast at 37C. After 1 month of ABLC, the antifungal therapy was switched to itraconazole oral solution and lopinavir/ritonavir was replaced with raltegravir. The patient was discharged and continued itraconazole for 10 months, with regular therapeutic drug monitoring until the CD4+ cell count increased to 200 cells/mmc. Today he has attained good clinical status with a complete immunological recovery and radiological resolution. Mucocutaneous lesions are no longer appreciable. Infectious Disease Clinic, AOU IRCCS San Martino-IST, University of Genoa (DISSAL), Genoa, Italy.

LLAMADO AL TAMIZAJE DE ESTOS PTES Y A LA PROFILAXIS.
Marzo 2019 LLAMADO AL TAMIZAJE DE ESTOS PTES Y A LA PROFILAXIS. Estudio retrospectivo multicéntrico en Guinea Francesa N= 22 casos (14 desenmascaramiento y 8 paradójicos) Tasa incidencia 0,74 casos por 1000 personas infectadas con VIH al año Media inicio de Sx pos TARV  11 días (7-40 días). CC: fiebre, cuadro inespecífico y enfermedad diseminada, manifestaciones mucocutáneas poco frecuentes (2/22  rash papular). Oxford IDSA: SUMMARY: Histoplasmosis-associated immune reconstitution inflammatory syndrome (IRIS) in people living with HIV (PLHIV) is rarely reported. Here we described a low incidence of histoplasmosis-associated IRIS along with a significant morbidity. Histoplasmosis screening strategy is required in PLHIV initiating antiretroviral therapy. Background Histoplasmosis is among the main AIDS-defining conditions in endemic areas. Although histoplasmosis has a worldwide distribution, histoplasmosis-associated immune reconstitution inflammatory syndrome (IRIS) in people living with HIV (PLHIV) is rarely reported. This study aimed to describe the incidence and features of histoplasmosis-associated IRIS in a cohort of PLHIV. Method A retrospective multicentric study was conducted in French Guiana from 01/01/1997 to 09/30/2017. The target population was represented by PLHIV who presented an episode of histoplasmosis within six months after antiretroviral therapy initiation. We used a consensual IRIS case definition, submitted to the agreement of 2 experts. Each case was described using a standardized questionnaire and all patients gave informed consent. Results Twenty two cases of histoplasmosis-associated IRIS were included (14 infectious/unmasking and 8 paradoxical) with an overall incidence rate of 0.74 cases per 1000 person-years HIV-infected (CI95%: ). Mean age was 40.5 years. Sex ratio M:F was 1.4. Median time to IRIS was 11 days [7-40] after antiretroviral therapy initiation. The main clinical presentation was fever, without any specific pattern, and disseminated disease. We reported 2 severe cases and partial or complete recovery at one month was the rule. Twenty-two cases were identified in the literature with similar characteristics. Discussion Histoplasmosis-associated IRIS incidence was low but generated significant morbidity in PLHIV. In endemic areas, screening for latent or subclinical histoplasmosis should be implemented before antiretroviral therapy initiation. __________- DISCUSSION With 22 cases we report a large retrospective case series of histoplasmosis-associated IRIS in PLHIV. With an overall incidence rate of 0.74 p1000 person-years HIV-infected, histoplasmosis-associated IRIS remains rare and stable over a 20-year period despite evolutions in HIV care and treatment. This incidence rate was lower than in reports on the frequent association of IRIS with other pathogens (i.e. Mycobacterium tuberculosis), among PLHIV with baseline CD4 counts <200 cells/μl(26). It is noteworthy that reviewing the medical files of all suspected cases, using a rigorous case definition and expert agreement, led to the exclusion of numerous cases. It resulted in lower incidence rate estimates when compared to the previously published estimates computed from the same cohort(27). The main clinical presentations revealed a non-specific and disseminated expression of the disease. Upon the clinical evaluation of the patients, the only pattern observed was the rapid progression of a subclinical or a previously treated disseminated histoplasmosis following the recent introduction of ART in an asymptomatic patient. Nonetheless, we observed a very rare case of IRIS associated with a placental histoplasmosis, which, to our knowledge, has never been described. H. capsulatum infection was probably only discovered because ART initiation and IRIS occurrence were associated with preterm birth. No specific treatment was given while waiting for the results of a placental fungal culture, which was positive one month after delivery, and followed by antifungal therapy in an asymptomatic patient at the time. Similarly, despite being premature, the newborn infant had a favorable outcome without any antifungal therapy and no investigations were performed to diagnose histoplasmosis. The management of paradoxical IRIS revealed that physicians’ did not discontinue ART and oral itraconazole for 6/8 patients. For two patients, both co-infected with P. jiroveci or CMV, physicians added to ART regimens a short course of corticosteroids or liposomal amphotericin B in a severe case requiring surgery, respectively. Regarding the management of infectious/unmasking IRIS, ART and antifungals continuation was the rule. Only 2 patients received corticosteroids. We reported no deaths, complete or partial recovery for all patients at one month after ART initiation. Two patients were admitted in ICU and labelled severe (one infectious/unmasking and one paradoxical IRIS). When considering the use of Liposomal Amphotericin B as a proxy for histoplasmosis-associated IRIS severity, we can add 9 severe IRIS cases, all infectious/unmasking out of one paradoxical IRIS, making a total of 11/22 IRIS cases that were severe or at least generated marked morbidity levels. When comparing histoplasmosis-associated IRIS cases in our study with those published to date, the main clinical presentations showed the same non-specific and disseminated disease pattern. Still, mucocutaneous manifestations were more frequent in cases issued from the literature (y en la literatura era 1 de 22 casos). Median time to IRIS after ART initiation was similar in both groups of paradoxical IRIS (30 days). The difference in the median time to ART after antifungal initiation (27 days in our study versus 40.5 days in the literature) may have no influence on the outcome. On the other hand, among infectious/unmasking IRIS cases, median time to IRIS after ART initiation was six times longer in cases from the literature (60 days) compared to those in our study (9 days), perhaps because of a lack of awareness of histoplasmosis. The influence of ART regimens on the occurrence of IRIS, notably the presence of PIs, was not significant in our study and was not evaluated because of missing data in IRIS cases from the literature. No deaths occurred in the month following IRIS symptoms’ onset in both case series. Similarly, both case series reported one patient each with 2 consecutive episodes of histoplasmosis-associated IRIS (23): an unusual but previously reported situation (28,29). ___ on infectious/unmasking histoplasmosis-associated IRIS give insights on the needs for effective and simple rapid diagnostic tests, to test and treat all PLHIV at the advanced stage of HIV disease in endemic areas for H. capsulatum before ART initiation. Only one Histoplasma antigen rapid diagnostic test in urine is commercially available but not yet fully distributed in endemic areas(32) and the developments on interferon-γ release assay (IGRA) to detect latent H. capsulatum infection are promising(33). Hence, to our knowledge, there are no reports on systematic screening studies regarding HIV-associated histoplasmosis Reports of severe cases of infectious/unmasking histoplasmosis-associated IRIS also call for the implementation of histoplasmosis primary prophylaxis in endemic areas. This attitude may avoid morbidity due to the flare-up of latent or subclinical HIV-associated histoplasmosis at the time of ART initiation. Following IDSA guidelines, itraconazole prophylaxis is recommended in PLHIV with a CD4count<150 cells/μl in endemic areas with histoplasmosis incidence >10 cases p100 patient-years(9). LLAMADO AL TAMIZAJE DE ESTOS PTES Y A LA PROFILAXIS. Clinical Infectious Diseases, ciz247,

Clinical Infectious Diseases, ciz247, https://doi. org/10

TARV: ¿Continuarla o suspenderla?
TARV mejora desenlace en VIH con histoplasmosis diseminada Pacientes con TARV que desarrollan IRIS – histoplasmosis diseminada, deben continuar TARV. IRIS paradójico  «Espere y observe»  Continuar terapia antifúngica+ TARV. Papel de esteroides no claro. IRIS por desenmascaramiento  Terapia antifúngica. Inicio de TARV luego de inicio terapia antifúngica  primeras 2 ss. Debido a que lo que se conoce sobre el IRIS asociado a histoplasmosis se limita a reportes de casos y series de casos, no se tiene claridad sobre cuándo debe iniciarse la ART una vez realizado el diagnóstico e instaurado el tratamiento para histoplasmosis. Lo que sí se conoce es que los pacientes que reciben ART presentan una respuesta clínica más favorable: Tobón et al. reportaron una respuesta clínica favorable en el 100% de los pacientes que estaban recibiendo ART en contraste con solo un 47% de los pacientes que no habían recibido terapia antirretroviral54. Por otro lado, se especula que la aparición del IRIS asociado a la histoplasmosis en pacientes que se encuentran recibiendo ART es una entidad poco frecuente, y cuando se presenta este síndrome, cursa con manifestaciones leves. Por tanto, las guías de la Sociedad Americana de Infectología sugieren que el tratamiento para el VIH no debe evitarse únicamente con el objetivo de prevenir el desarrollo del IRIS55. ___________________ Antiretroviral therapy substantially improves the outcomes of HIV-infected people with disseminated histoplasmosis. Additionally, there is evidence suggesting that patients on ART who develop disseminated histoplasmosis IRIS should continue on the ART. __________________ The management of IRIS cases is not standardized and may depend on the causative pathogen, disease and IRIS pathogenesis. When considering paradoxical IRIS, authors report that an initial “wait-and-see” attitude in the case of non-severe tuberculosis-associated IRIS remains an interesting strategy since the outcome was favourable regardless of the therapeutic strategies employed(30). But, for instance, this “wait-and-see” strategy may not be applicable to crytpococcal meningitis paradoxical IRIS(31). On the other hand, in case of infectious/unmasking IRIS, the treatment of the causative pathogen together with ART continuation is probably the rule. The impact of corticosteroids on IRIS outcome is either unclear or useless. Hence, time to ART after antifungal therapy is not clearly evaluated exposing patients to paradoxical IRIS. The Infectious Disease Society of America (IDSA) recommendations(9) stated that there are no reasons to wait over a month to introduce ART, mainly because PLHIV at the advanced stage of HIV disease are at greater risk of experiencing lethal opportunistic infections. A two weeks delay after antifungal initiation together with significant clinical improvements in PLHIV experiencing HIV-associated histoplasmosis might be a reasonable minimum to avoid intense inflammatory responses. Furthermore, whether or not ART should be initiated according to the level of Histoplasma antigen concentration in the blood has never been assessed. Following IDSA guidelines, itraconazole prophylaxis is recommended in PLHIV with a CD4count<150 cells/μl in endemic areas with histoplasmosis incidence >10 cases p100 patient-years(9). __________________- In cases of unmasking IRIS, the OI needs to be diagnosed and treated appropriately with antimicrobials. HAART should be continued. In paradoxical reactions, it is first important to consider differential diagnoses, including antimicrobial resistance, a drug reaction, or another untreated infection. Management of these patients involves continuing HAART and OI treatment, symptomatic therapy, and consideration of corticosteroids in severe cases. Consideration should be given to stopping HAART in life-threatening cases [42]. Infectio. 2012;16(Supl 3): 51-58 Clinical Infectious Diseases, ciz247,

Inicio de TARV e IRIS Pistas en IRIS Empeoramiento clínico
Adecuada adherencia al tratamiento y niveles Antígeno en disminución Cultivo negativo a pesar de evidencia histopatológica No respuesta a intensificación de terapia Respuesta al manejo inmunosupresor Guidelines for Prevention and Treatment of Opportunistic. Infections in HIV-Infected Adults and Adolescents

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