n2nd part n u §Opportunistic infections §Tuberculosis §PCP §Cryptococcosis §MAC u u n Opportunistic infections nDecrease in number of CD4 lymphocytes is condition for development of opportunistic infections n nRisk is started, when number of CD4 lymphocytes drops to number 500 of CD4 lymphocytes/mm3 sken1 CD4+ lymphocytes depletion = condition for development of opportunistic infections CD4+ count early symptomatic infection-OI late symptomatic infection - AIDS years A1 B2 C3 CD4 count and opportunistic infection TUBERCULOSIS - the most important - the most common OI Epidemiology •One-third of the world´s population is infected with TB •HIV infection has had a big impact in increasing the numbers of patients affected with disease caused by TB •TB is the most important severe opportunistic infection among patients with HIV in developing countries Global_EstimatedTB06_ITH2009 TB – estimated new cases (per 100 000) Tuberculosis •Is a leading cause of HIV-related deaths worldwide •In some countries with higher HIV preavalence, up to 80% of people with TB test positive for HIV •Globally approximately 30% of HIV infected persons are estimated to have n latent TB infection Tuberculosis •In last years, there were an estimated n 1,4 million new cases of TB n among persons with HIV infection n •TB accounted for n 23% of AIDS-related deaths TBincidence_2009.png TB – droplet infection nTB is transmissible to both people uwith HIV infection uuninfected persons n can be treated and can be prevented tbc.jpg šíření TB.jpg Clinical Manifestations nMyco TB n nIs highly contagious nLeads to a number of serious medical syndromes affecting, at time, n most of the organ systems TB +.jpg Myco TB can causes: 1.Pulmonary disease tPneumonia tCavitary disease 2.Extrapulmonary disease §Adenitis („scrofula“) §Otitis media §Laryngitis §Miliary TB §Meningitis §Skeletal TB §Gastrointestinal TB §Renal TB… o Pulmonary TB nCavities in the lungs (X-ray of thorax) n nMiliary TB tbc kaverny.jpeg TBC miliární - Kopie.jpg Tb adenitis („scrofula“) scrofula TB 3.jpg scrofula scrofula TB 2.jpg TB absces in brain a13f01a.gif Skeletal TB - destruction of the lumbar vertebrae - skeleton of the Great Moravian Empire tb pateře z velkomoravské říše.jpg TB kostí.jpg TB kostí II.jpg Destruction of the thoracic vertebrae (skeleton of the Old Egypt Empire) TB v ČR.png Number of TB in Czech Republic nMycobacterium tuberculosis bacteria (G+) is acid-fast, appearing red on a Ziehl-Neelsen stain n nM. tuberculosis bacteria (G+) – ultrastructural details (electron micrograph) TBC-Ziel-Nilsen.jpg 9997_lores - TBC.jpg Primary prophylaxis conditions pathogen drug CD4+ any + TB exposure (when HIV+ individual is in exposure of TB we must start primary prophylaxis) M. tuberculosis isoniazid (+pyridoxin), rifampicin, pyrazinamid, ethambutol Myco TB is highly contagious !!! n nPneumocystis jiroveci npneumonia Pneumocystis jiroveci nIs an opportunistic pathogen, n the natural habitant of which is the lung n nThe organism is an important cause n of pneumonia in the compromised host n nThe organism can be found in other organs and tissues n CD4 count and opportunistic infection sken1 CD4+ lymphocytes depletion – gradual loss of number of CD4 cells CD4+ count primary HIV infection asymptomatic infection early symptomatic infection late symptomatic infection final stadium years A1 B2 C3 Pneumocystis jiroveci nHas a worldwide distribution n nSerologic serveys indicate that already most healthy children have been esposed to the organism n nIt means that we meet with this organism in early childhood n nTaxonomy – the fungal kingdom Risk Factors nPn. carinii jiroveci occurs in the following hosts: npremature, malnourished infants nchildren with primary immunodeficiency disease npatients receiving corticosteroids n or other immunosuppressive therapy npatiens with autoimmune diseases with disorder of immune system nseverely immunosuppressed patients with hematologic or other malignancies, organ transplantation, and so forth nHIV-infected individuals CD4 count and opportunistic infection Incidence nPCP accounted for 42% of all AIDS-indicator diseases before ART n nIncidence of PCP in this population is declining (with ART and prophylaxis) n nBut incidence of extrapulmonary Pn. carinii jiroveci is increasing Extrapulmonary Pn.carinii jiroveci infection ninvolves in fewer than 3% of cases. nLymph nodes (in up to 50% of cases) nSpleen nLiver nBone marrow nGI and genitourinary tracts nAdrenal and thyroid glands nHeart, pancreas, eyes, ears, skin… Incubation Period n n nOn the basis of animal studies, the incubation period is thought to be n n from 4 to 8 weeks Symptoms nThe clinical picture is quite variable n nHIV-infected patients are usually ill n for several weeks or longer n and have relatively subtle and light manifestations n nCan mimic influenza-like illness tOver a few weeks or months Typical Symptoms §Patients with PCP usually develop the following: § Dyspnea § Mild fever § Nonproductive cough § nPhysical findings of PCP include the following: § Tachypnea § Tachycardia § Cyanosis nLung auscultation is usually unremarkable n n G:\2000-2012 TVORBA\2009 tvorba\PCP.jpg Alveolocapillary membrane -characteristic exudate is in the inter alveolar space Differential Diagnosis nThe differential diagnosis of PCP is very broad and includes § infectious diseases tAtypical pneumonia (due to Mycoplasma or Chlamydia spp, etc.) tAtypical presentation of pneumococcal or fungal pneumonia tLegionnaires´ disease tTuberculosis tViral pneumonia § nand also can mimic § noninfectious diseases tCongestive heart disease tKaposi´s sarcoma tLymphoma involving the lungs tPulmonary embolism t… § Laboratory n nThere is no reliable way to cultivate n the organism in vitro n nA definitive is made by histopathologic n staining, which selectively stain n the wall of Pn. carinii jiroveci, n cysts or nuclei n nPCR technique which demonstrate nuclei acid Cysts of Pn. Jiroveci - Methenamine silver stain. In smear from bronchoalveolar lavage. Characteristic cysts with cup forms and cyst wall thickenings Pn. jiroveci – trophozoites (growth stage), Giemsa-stained, large nuclei Pn.carinii jiroveci – immunofluorescence with monoclonal antibodies is more sensitive than traditional staining Laboratory nLDH nElevated serum concentrations of lactate dehydrogenase have been reported but are not specific to Pn. Carinii infection nLeucocytes nThe white blood cell count is low nOxygen saturation is very low nIs probably the most sensitive noninvasive test for dg. PCP nArterial blood gases demonstrated §Hypoxia §An increased alveolar-arterial oxygen gradient n Imaging nThe classic findings on chest radiography consist of bilateral diffuse infiltrates involving the perihilar regions. n nAtypical manifestations also have been reported. n nEarly in the course of pneumocystosis, the chest radiograph may be normal. Pneumocystis jiroveci pneumonia (PCP) HRCT PCP a nekrozy.jpg HR CT imaging – the most important imaging method shows white glass picture Diagnostic/testing procedures nFiberoptic bronchoscopy nWith bronchoalveolar lavage (and investigation of bronchoalveolar fluid by PCR) remains the mainstay of PCP diagnosis nSputum nis a simple, noninvasive technique, but its sensitivity has extremely low nTransbronchial biopsy and open lung biopsy nare the most invasive, are reserved for situations in which a diagnosis cannot be made by lavage n n n Complications nIn the typical case of untreated PCP, n progressive respiratory compromise n leads to death. n nTherapy is most effective when instituted n early in the course of the disease, before n there is extensive alveolar damage. n Main treatment nTrimethoprim-sulfamethoxazol n nIs the drug of the first choice for all forms of Pn. Carinii infection n nIt is administered intravenously (orally) at a dosage 120 mg of TSX/kg/d in four divide doses nGlucocorticoids n nAdministration of glucocorticoids to HIV-infected patients with moderate to severe pneumocystosis can improve the rate of survival nThe recommended regimen: n 40 mg prednisone PO twice daily, n with tapering to a dose of 20 mg/d n over a 3-week period Duration of treatment nnon-HIV-infected patients nTreatment of pneumocystosis should be continued for 21 days n nHIV-infected patients nTreatment of pneumocystosis should be continued for 21 days n Alternative treatment nPentamidine n 4 mg/kg/d by slow intravenous infusion nClindamycin nPrimaquine n avoided in patients with glucose-6- n phosphate dehydrogenase deficiency nTrimethoprim + dapson nAtovaquone n Primary prophylaxis nIs indicated for HIV-infected patients at high risk of developing pneumocystosis n n CD4+ lymphocyte count < 200/mm3 n nIs indicated for other immunocompromised hosts n in known risk groups: §Bone marrow transplant recipients §With acute lymphoblastic leukemia… n Secondary prophylaxis nIs indicated for all patients who have recovered from PCP tProphylactic regimen tTrimethoprim-sulfamethoxazol t (160mg of trimethoprim) per day t tAlternative regimens tDapsone (50mg daily), pyrimethamine (50mg once per week), and folinic acid (24mg once per week) tDapsone (100mg daily) tNebulized pentamidine t (300mg once per month via nebulizer) n Primary prophylaxis conditions pathogen drug CD4+ any + TB exposure M. tuberculosis isoniazid (+pyridoxin), rifampicin, pyrazinamid, ethambutol CD4+ < 200/mm3 Pn. carinii jiroveci co-trimoxazol, pentamidine (aerosol), dapson CRYPTOCOCCOSIS n nIs a systemic infection caused by the yeastlike fungus n n Cryptococcus neoformans Cryptococcus neoformans nAn encapsulated, yeastlike fungus that reproduces by budding nA saprobe in nature, with a worldwide distribution nSoil may also contain the fungus, especially if the soil is contaminated with bird droppings nThe portal of entry is the lung cryptococcus 5.jpg Epidemiology nAIDS is the major predisposing factor nAIDS-associated cases usually occur when CD4+ T-lymphocyte counts fall below 200 cells/mm3 n usually bellow 100 cells/mm3 PHIL_3771_lores-crypto.jpg Cryptococcus neoformans – a light India ink staining preparation CD4 count and opportunistic infection nRisk factors n nNumbet of CD4+ lymphocyte nOrgan transplantation (the second most frequent risk factor), largely attributable to the use of corticosteroids and immunosippresive drugs. nLymphoreticular malignancies (especially Hodgkin´s disease) nHigh-dose corticosteroids or other immunosuppresive agents nSarcoidosis or diaetes mellitus nAbout half of patients with cryptococcosis lack apparent predisposing factors Clinical manifestations of CNS cryptococosis nThe onset of CNS cryptococcosis may be acute or insidious nThose who have a more chronic course have waxing and waning manifestations over weeks or months, often with completely asymptomatic periods n nSymptoms include: nConfusion, dizziness, headache, irritability nNausea, obtundation nSeizures, somnolence, visual loss n nSome HIV+ patients have minimal or no symptoms at the time of presentation nPatients are often afebrile or have a mildly elevated temperature nMost patients have minimal or no nuchal rigidity nPapilledema is noted in up to one-third of the cases CNS cryptococcosis nAbnornmalities in cerebrospinal fluid n opening pressure n¯ glucose n protein concentration n leukocyte counts n nCryptococci grow in culture n nLatex agglutination ndetects antigen in CSF or serum (or both) from 90% or more of the HIV-infected patients with cryptococcal meningitis n PHIL_3199_lores-crypto.jpg This SABHI agar slant culture is growing Cr. Neoformans grown at 37oC. 28 Cr. neoformans in CSF Pulmonary cryptococcosis nAsymptomatic nSymptomatic n – with production of only scant, n sometimes blood-streaked sputum uFever uCough and dyspnea uPleuritic chest pain (often) uRoentgenographic findings of lymphadenopathy or pleural effusions, with diffuse mixed interstitial and intraalveolar infiltrates n Laboratory nPulmonary cryptococcosis nThe isolation of C. neoformans from respiratory specimens nIt can represent a pulmonary infection nIt can represent an asymptomatic carriage Other organs n nBesides the respiratory system and the CNS, cryptococcosis may involve a number of other organs: n nBone (causing lesions that can be mistaken for neoplasms) nEye nHeart (leading to pericarditis, myocarditis, endocarditis) nSinus nSkin (causing nonspecific lesions that could be the first signs of infection) nUrinary tract (as an unusual cause of pyelonephritis) n Extrapulmonary cryptoccocosis - skin n 16 cryptococcus.jpg Primary prophylaxis conditions pathogen drug CD4+ any + TB exposure M. tuberculosis isoniazid (+pyridoxin), rifampicin, pyrazinamid, ethambutol CD4+ < 200/mm3 Pn. jiroveci co-trimoxazol, pentamidine (aerosol), dapson CD4+ < 150/mm3 + antibody to Toxoplasma positive Toxoplasma gondii co-trimoxazol, dapson, pyrimethamin(+folinat) CD4+ < 75/mm3 M. avium-intracellulare clarithromycin, azitromycin, rifabutin conditions pathogen drug CD4+ < 50/mm3 Cytomegalovirus Ganciclovir (PO) Candida sp. fluconazol, itraconazol Cryptococcus neoformans fluconazol, itraconazol CD4+ < 50/mm3 + endemic area of Histoplasma Histoplasma capsulatum itraconazol, fluconazol CD4+ < 50/mm3 + endemic area of Coccidioides Coccidioides immitis fluconazol, itraconazol Disseminated Mycobacterium avium complex Mycobacterium avium complex (MAC) nComprises two closely related organisms: nMycobacterim avium nMycobacterium intracellulare n nMAC organisms are common in many environmental sites: nNatural water sources nIndoor water systems, pools, hot tubes… nSoil nAnimals Disseminated Mycobacterium avium complex nMAC is acquired by nInhalation nIngestion n80 – 90% of infections are acquired by ingestion (water, soil, animals – food…) n nRisk nSevere depression of the CD4 lymph. nRarely in patients with greater than 100 CD4/mm3 nMedian CD4+ lymf. count among patients with AIDS is 10 cells/ml n n n Mycobacterium avium complex nIs relatively avirulent in the normal host nThey cause od disseminate disease in AIDS patients nThe organisms grow slowly nThe organisms penetrate the gut wall, nsubsequently are phagocytized by macrophages and other RES cells n®mesenteric adenopathy n®hematologic dissemination occurs (after 6-12 months) n Disseminated Mycobacterium avium complex nClinical presentation n nFever, night sweats nCachexia nPain of abdomen nSevere anemia, elevation of serum alkaline phosphatase nDisease leads to death by inanition •Decreased caloric intake •Increased metabolic demand •Median survival after diagnosis was only 134 days n Disseminated Mycobacterium avium complex nCommon organs involved: n nLiver, spleen (hepatosplenomegali) •Little elevation of bili, AST, ALT •High elevation of (20-40x) ALP, GGT n nHepatic biopsy •Histologic picture inthe liver does not show marked abnormality, suggesting interference with enzyme metabolism rather than hepatic tissue destruction CT of abdomen •Hepatomegaly •Splenomegaly •Retroperitoneal and mesenterial lymfadenopathy •Increase portobilium CT of abdomen transversally Multiple small focuses in hepar (small abscesses?) and dilatation of intrahepat. ductus biliares. Increase of hepar. Increase of lien. Retroperitoneal and mesenterial lymphadenopathy. CT of abdomen Multiple small focuses in hepar (small abscesses?) and dilatation of intrahepat. ductus biliares •Increase of hepar •Increase of lien •Retroperitoneal and mesenterial lymphadenopathy •Susp. thickness of caecum and c.ascendens Disseminated Mycobacterium avium complex nLymphnodes n nBowel wall with severe pain of abdomen, but histologically, epithelial cells show only mild inflammatory changes, and ulceration is unmommon n nBone marrow tThe mechanism of the severe anemia seen is not well understood tBone marrow involvement can be minimal tClinical response to exogenous erythropoietin is unpredictable t Disseminated Mycobacterium avium complex t nLess commonly organs involved: n nLungs nAdrenals nStomach nCentral nervous system n (not typical environmental for mycobacterium) n nDuodenum – detail – surface – bk. Numerous of acidoresistant sticks in cytoplasma of macrofages (staining Ziehl-Nielsen). C:\Users\Svatava\SVATAVA SNOPKOVÁ 30.5.2010\AKT. TVORBA - 20.9.2010\MAC-ABBOTT\MAC-Nataša, mikro\MAC - mikro\duodenum-detail-povrch-bk.png nDuodenum – detail. Mucosa of duodenum, accumulation of macrofages, inflammatory infiltration by lymfoplasmocytes. C:\Users\Svatava\SVATAVA SNOPKOVÁ 30.5.2010\AKT. TVORBA - 20.9.2010\MAC-ABBOTT\MAC-Nataša, mikro\MAC - mikro\duodenum-detail.png Post mortem n nHepar tweight 3130 g (normal 1500g) nLien tweight 530 g (normal max 250 g) nCerebrum tweight 1302 g (normal 1500 g) Disseminated Mycobacterium avium complex n P1010001.JPG nNecrosis of intrahepatic biliary ducts P1010011.JPG nSlight wet brain, well-kept structure of cortex. Slightly defibering of neuropil. n n n nMultiple capillaries, subarachnoideal inflamatory celluolus infiltration. Mycobacteria negative – special staining. P1010005.JPG P1010008.JPG Treatment nCombination therapy is essential nFailure rates and mortality remained very high nClarithromycin, rifabutin, ethambutol nGreater than 17% of strains of MAC had baseline resistance to macrolides n n n n nThank you for your attention….