Harrison manual of medicine 19e 2016 2

Harrison manual of medicine 19e 2016 1 Harrison manual of medicine 19e 2016 1 Harrison manual of medicine 19e 2016 1 Harrison manual of medicine 19e 2016 1 Harrison manual of medicine 19e 2016 1 Harrison manual of medicine 19e 2016 1 Harrison manual of medicine 19e 2016 1 Harrison manual of medicine 19e 2016 1 Harrison manual of medicine 19e 2016 1

Fungal Infections 579 HMIHII RECOMMENDATIONS FOR THE TREATMENT OF HISTOPLASMOSIS Type of Histoplasmosis Treatment Recommendations Acute pul monary, moderate to severe illness with diffuse infi ltrates and/or hypoxemia Lipid AmB (3-5 mg/ kg per day) ± glucocorticoids for -2 weeks; then itraconazole (200 mg bid) for weeks Monitor renal and hepatic function ltraconazole (200 mg qd or bid) for at least months Monitor hepatic fu nction Chronic/cavitary pul monary Progressive disseminated Centra l nervous system Comments Pts with mild cases usually recover without therapy, but itraconazole shou ld be considered if the pt' s condi­ tion has not improved after month Continue treatment until radiographic findings show no further improvement Monitor for relapse after treatment is stopped Lipid AmB (3-5 mg/kg Liposomal AmB is preferred, but the AmB lipid complex per day) for -2 weeks; then itraconazole (200 may be used because of cost Chronic maintenance therapy mg bid) for at least months Monitor renal may be necessary if the and hepatic function degree of immunosu ppres­ sion cannot be reduced A longer course of lipid AmB Liposomal AmB (5 mg/ is recommended because of kg per day) for 4-6 weeks; then itraconazole the high risk of relapse ltra­ (200 mg bid or tid) for at conazole should be contin­ least months Moni­ ued until cerebrospinal fl uid or CT abnormalities clear tor renal and hepatic fu nction Abbreviation: AmB, amphotericin B • Direct exposure to soil harboring Coccidioides increases risk, but infection, which results from inhalation of airborne arthroconidia, can occur without overt soil exposure and may be related to other climatic factors (e.g., periods of dryness after rainy seasons) Clinical Manifestations Approximately 60% of infected pts are asymptomatic; the remaining 40% have primarily pulmonary disease characterized by fever, cough, and pleuritic chest pain • Primary pulmonary infection is sometimes associated with erythema nodosum, erythema multiforme, arthralgias, and arthritis - A history of night sweats, profound fatigue, eosinophilia, and hilar or mediastinal lymphadenopathy suggests the disease - Pneumonic complications include pulmonary nodules (resembling pulmonary malignancies) and pulmonary cavities (a thin-walled lesion in a bronchus that is associated with cough, hemoptysis, and pleuritic chest pain) • Disseminated infection affects < I % of infected pts, most commonly pts with depressed cellular immunity and pregnant women - Common sites for dissemination include bone, skin, joint, soft tissue, and meninges - Pts with meningitis present with persistent headache, lethargy, confusion, mild to moderate nuchal rigidity, and CSF with lymphocytic pleocytosis and profound hypoglycorrhachia The mortality rate is - 00% without treatment 580 Infectious Diseases Diagnosis Clinical findings that suggest coccidioidomycosis include eosinophilia, hilar or mediastinal adenopathy on radiographic imaging, marked fatigue, and failure to improve with antibiotic therapy Serology and culture are the primary means of diagnosis Alert the laboratory of the possible diagnosis to avoid exposure • Tube-precipitin (TP) and complement-fixation (CF) assays, immunodiffusion, and an enzyme immunoassay (EIA) are available to detect IgM and IgG antibodies - TP antibody does not gauge disease progression and is not found in CSE - Rising CF titers in serum are associated with clinical progression, and CF antibody in CSF indicates meningitis - EIA frequently yields false-positive results • Examination of sputum or other respiratory fluids after Papanicolaou or Gomori methenamine silver staining reveals spherules in many pts with pulmonary disease • The vast majority of pts with coccidioidomycosis not require treatment Exceptions include the following: - Pts with focal primary pneumonia and underlying cel lular immunodeficiency or prolonged symptoms (i.e., symptoms persisting for ;::2 months, night sweats occurring for >3 weeks, weight loss of > 0%, a serum CF antibody titer of > : 6, and extensive pulmonary involvement apparent on CXR) should be treated with fluconazole (;,,400 mg/d) or itraconazole (400-600 mg/d) - Pts with diffuse pulmonary disease are often treated initially with AmB (deoxycholate, 0.7-1 mg/kg IV qd; liposomal, mg/kg IV qd), with a switch to prolonged therapy with an oral triazole once clinical improvement occurs - Pts with chronic pulmonary disease or disseminated infection are treated with a triazole for ;,, year Relapse occurs in 5-30% of individuals once therapy is discontinued - Pts with meningitis require lifelong triazole therapy; fluconazole is the drug of choice If triazole therapy fails, intrathecal or intraventricular AmB may be used Relapse occurs in 80% of pts when therapy is stopped BLASTOMYCOSIS Microbiology and Epidemiology Blastomyces dermatitidis is a dimorphic fungus that is found in the southeastern and south-central states bordering the Mississippi and Ohio river basins, in areas of the United States and Canada bordering the Great Lakes and the St Lawrence River, and sporadically in Africa, the Middle East, and India Infection is caused by inhalation of Blastomyces from moist soil rich in organic debris Clinical Manifestations Acute pulmonary infection can present as abrupt-onset fever, chills, pleuritic chest pain, myalgias, and arthralgias However, most pts with pulmonary blastomycosis have chronic indolent pneumonia with fever, weight loss, productive cough, and hemoptysis Skin disease is common and can present as verrucous (more common) or ulcerative lesions Blastomycosis can include osteomyelitis in one-fourth of infec­ tions and CNS disease in -40% of pts with AIDS Diagnosis Smears of clinical samples or cultures of sputum, bronchial washings, pus, or tissue are required for diagnosis Antigen detection in urine and serum may help diagnose infection and monitor pts during therapy Fungal Infections 581 • Every pt should be treated because of the high risk of dissemination - For immunocompetent pts with nonsevere disease that does not involve the CNS, itraconazole (200-400 mg/d for 6-1 months) is recommended - lmmunocompetent pts with severe disease or CNS manifestations should be treated initially with AmB (deoxycholate, 0.7-1 mg/kg IV qd; liposomal, 3-5 mg/kg IV qd); once their clinical condition improves, therapy can be switched to itraconazole (or, for those with CNS disease, fluconazole, 800 mg/d) - lmmunocompromised pts with any form of infection should be treated initial ly with AmB, with a switch to a triazole, as above, once clinical improve­ ment has occurred MALASSEZIA INFECTION Malassezia species are components of the normal skin flora and can cause tinea (pityriasis) versicolor, round scaly patches of hypo- or hyperpigmented skin on the neck, chest, or upper arms M furfur causes catheter-related fungemia in premature neonates receiving IV lipids by central venous catheter Topical creams and lotions for weeks are effective in treating superficial Malassezia infections; fungemia caused by Malassezia species is treated with AmB or fluconazole, prompt removal of the catheter, and discontinuation of the lipid infusion SPOROTRICHOSIS Microbiology and Epidemiology Sporothrix schenckii is a dimorphic fungus found worldwide in soil, on plants, and on animals Infection, which results from inoculation of the organism into the skin, is most common among people who participate in landscaping, gardening, or tree farming Clinical Manifestations Lymphocutaneous sporotrichosis involves secondary lesions (papules that are not very painful and often ulcerate) developing along lymphatic channels proximally from the initial site of inoculation Other presentations include a fixed lesion (ver­ rucous or ulcerative) at the initial site of inoculation without lym phatic spread, osteoarticular disease (chronic synovitis or septic arthritis in alcoholics), pulmonary disease (most common among pts with chronic obstructive pulmonary disease), and disseminated disease (numerous skin lesions with occasional spread to visceral organs in immunocompromised pts) Diagnosis Culture of material from a skin lesion or histopathologic examination of a skin biopsy sample can confirm the diagnosis IMt\WUII SPORO RIC OSIS • Cutaneous and lymphocutaneous sporotrichosis is treated with itraconazole (200 mg/d) until 2-4 weeks after lesions resolve, usually for a total of 3-6 months • For extracutaneous disease, itraconazole (200 mg bid for � months) can be given, but initial therapy with liposomal AmB (3-5 mg/kg qd) is more effective for life-threatening pulmonary disease or disseminated infection PARACOCCIDIOIDOMYCOSIS Paracoccidioidomycosis (South American blastomycosis) is caused by Paracoc­ cidioides brasiliensis, a dimorphic fungus acquired by inhalation from environmental 582 Infectious Diseases sources Acute infection occurs in young or immunocompromised pts and mani­ fests as disseminated infection of the reticuloendothelial system Chronic infection accounts for 90% of cases and presents primarily as progressive pulmonary disease with occasional ulcerative and nodular mucocutaneous lesions in the nose and mouth Diagnosis relies on culture of the organism Itraconazole ( 100-200 mg/d for 6- 12 months) is effective, but AmB may be required for seriously ill pts PENICILLIOSIS Penicillium marneffei is a leading cause of opportunistic infection in pts with immu­ nocompromise (e.g., due to AIDS) in Southeast Asia and is acquired by spore inha­ lation Clinical manifestations are similar to those of disseminated histoplasmosis, with fever, fatigue, weight loss, lym phadenopathy, hepatomegaly, and skin lesions resembling molluscum contagiosum The organism grows readily in culture and produces a distinctive red pigment AmB is the initial treatment of choice for severely ill pts; less severe disease may be treated with itraconazole (200 mg bid for 12 weeks) Suppressive therapy with itraconazole (200 mg/d) may be indicated for pts with HIV infection or AIDS FUSARIOSIS Fusarium species are found worldwide in soil and on plants; inhalation, ingestion, and direct inoculation of spores can cause disease, particularly disseminated disease in immunocompromised pts Fusariosis is angioinvasive and has clinical manifes­ tations similar to those of aspergillosis One difference is that painful nodular or necrotic skin lesions are extremely common with disseminated fusariosis Blood cultures are positive in 50% of cases; the organism is difficult to differentiate from Aspergillus in tissue Fusarium species are often resistant to antifungal agents; lipo­ somal AmB (�5 mg/kg qd), voriconazole (200-400 mg bid), or posaconazole (300 mg/d) is recommended Even with treatment, mortality rates are -50% SCEDOSPORIOSIS Pseudallescheria boydii, Scedosporium apiospermum, and S prolificans are molds that are angioinvasive, causing pneumonia and widespread dissemination with abscesses (including brain abscess) in immunocompromised hosts Most disseminated infec­ tions are fatal These organisms are resistant to AmB, echinocandins, and some azoles, but some infections have been cured with voriconazole DERMATOPHYTOSIS See Chap 60 For a more detailed discussion, see Edwards JE Jr: Diag nosis and Treatment of Fungal I nfections, Chap 235, p 329; Hage CA, Wheat LJ: H istoplasmosis, Chap 236, p 332; Ampel NM: Coccidioidomycosis, Chap 237, p 334; Sullivan DC, Nolan RL I l l : Blasto­ mycosis, Chap 238, p 337; Casadeva l l A: Cryptococ­ cosis, Chap 239, p 339; Edwards JE Jr: Candidiasis, Chap 240, p 342; Denning DW: Aspergil losis, Chap 241 , p 345; Spel l berg B, I brahim AS: Mucormycosis, Chap 242, p 350; Kauffman CA: Su perficial Mycoses and Less Com mon Systemic Mycoses, Chap 243, p 353, in HPIM-1 Pneumocystis Infections 583 Pneumocystis Infections Pneumocystis, an opportunistic fungal pulmonary pathogen, is an important cause of pneumonia in immunocompromised hosts MICROBIOLOGY • P jirovecii infects humans, whereas P carinii-the original species described­ infects rodents • Developmental stages include the small trophic form, the cyst, and the intermediate precyst stage EPIDEMIOLOGY • Pneumocystis is found worldwide, and most people are exposed to the organism early in life • Infections resulting from environmental sources and person-to-person transmis­ sion have been demonstrated; the role of airborne transmission is unclear • Defects in cellular and humoral immunity (e.g., due to HIV infection, malignancy, transplantation, irnmunosuppressive medications) predispose to Pneumocystis pneumonia (PCP) The incidence among HIV-infected pts is inversely related to the CD4+ T-cell count: �80% of cases occur at counts l year later • RBCs infected with P falciparum may exhibit cytoadherence (attachment to venular and capillary endothelium), rosetting (adherence to uninfected RBCs), and agglu­ tination (adherence to other infected RBCs) The result is sequestration of P fal­ ciparum in vital organs, with consequent underestimation (through parasitemia determinations) of parasite numbers in the body Sequestration is central to the pathogenesis of falciparum malaria but is not evident in the other human malarias • In nonimmune individuals, infection triggers nonspecific host defense mechanisms such as increased splenic filtration Protozoa! Infections 587 - With repeated exposure to malaria, pts develop resistance to high-level parasit­ emia and disease but not to infection - Hemoglobinopathies (e.g., sickle cell disease, ovalocytosis, thalassemia) and G6PD deficiency are more common in endemic areas and protect against death from malaria Clinical Manifestations Pts initially develop nonspecific symptoms (e.g., headache, fatigue, myalgias) that are followed by fever • Febrile paroxysms at regular intervals are unusual and suggest infection with P vivax or P ovale • Splenomegaly, hepatomegaly, mild anemia, and jaundice may develop • The diagnosis of severe falciparum malaria requires one or more of the following: impaired consciousness/coma, severe normocytic anemia, renal failure, pulmonary edema, ARDS, circulatory shock, DIC, spontaneous bleeding, acidosis, hemoglo­ binuria, jaundice, repeated generalized convulsions, and a parasitemia level of >5% - Cerebral malaria manifests as diffuse symmetric encephalopathy, typically without focal neurologic signs - Coma is an ominous sign associated with mortality rates of -20% • Pregnant women have unusually severe illness Premature labor, fetal distress, still­ birth, and delivery of low-birth-weight infants are common • Tropical splenomegaly (hyperreactive malarial splenomegaly) may result as a chronic complication of malaria and is characterized by massive splenomegaly, hepatomegaly, and an abnormal immunologic response to infection Diagnosis Although antibody-based diagnostic tests are being used with increasing frequency, demonstration of asexual forms of the parasite on peripheral-blood smears is required for diagnosis • Thick and thin smears should be examined; thick smears and the less sensitive thin smears detect parasitemia levels as low as 0.00 % and 8 µg/ml, increased QT intervals (>0.6 s), or QRS widening by >25% is an indication for slowing the infusion rate • Exchange transfusions can be considered for severely ill pts, although indica­ tions for their use are not yet agreed upon • All pts with severe malaria shou ld receive a continuous infusion of dextrose U nconscious pts should have blood g l ucose levels measured q4-6h • Parasite counts and hematocrits for pts with severe malaria and pts with uncom­ plicated disease shou ld be measured q6-1 2h and q24h, respectively • Primaquine (0.5 mg of base/kg for days) eradicates persistent liver stages and prevents relapse in P vivax or P ovate infection G6PD deficiency must be ruled out before treatment 588 Infectious Diseases HMIHIM REGIMENS FOR THE TREATMENT OF MALARIA· Type of Disease or Treatment U ncomplicated Malaria Known chloroquinesensitive strains of Plasmodium vivax, P malariae, P ova/e, P knowlesi, P falciparum Radical treatment for P vivax or P ovate infection Sensitive P falciparum malaria' Regimen(s) Chloroquine (1 O mg of base/kg stat fol lowed by mg/kg at 2, 24, and 36 h or by mg/kg at 24 h and mg/kg at 48 h) or Amodiaquine (1 0-1 mg of base/kg qd for days) In addition to chloroquine or amodiaquine as detailed above, primaquine (0.5 mg of base/kg qd in tropical regions and 0.25 mg/kg for temperate­ origin P vivax) should be given for 14 days to prevent relapse In mild G6PD deficiency, 0.75 mg of base/kg should be given once weekly for weeks Primaquine should not be given in severe G6PD deficiency Artesunated (4 mg/kg qd for days) plus sulfadoxine (25 mg/kg)/pyrimethamine (1 25 mg/kg) as a single dose or Multidrug-resistant P falciparum malaria Artesunated (4 mg/kg qd for days) plus amodia­ quine (1 O mg of base/kg qd for days)' Either artemether-lumefantrined (1 5/9 mg/kg bid for days with food) or Artesunated (4 mg/kg qd for days) plus mefloquine (24-25 mg of base/kg-either mg/kg qd for days or mg/kg on day and then mg/kg on day 3)' or Dihydroartemisinin-piperaquined (2.5/20 mg/kg qd for days) Second-line treatment/ Either artesunated (2 mg/kg qd for days) or quinine treatment of imported (1 mg of salt/kg tid for days) plus of the following 3: malaria Tetracycline' (4 mg/kg qid for days) Doxycycline' (3 mg/kg qd for days) Clindamycin (1 O mg/kg bid for days) or Atovaquone-proguanil (20/8 mg/kg qd for days with food) Severe Falciparum Malaria• Artesunated (2.4 mg/kg stat IV followed by 2.4 mg/kg at and 24 h and then daily if necessary) h or, if unavailable, Artemetherd (3.2 mg/kg stat IM followed by mg/ kg qd) or, if unavailable, (Continued) ... mg/kg of base (8.3 mg of PO once weekly, up to maxi adult dose of 300 mg of ba5 �8 years of age: mg/kg, Uf adult dose mg of base/kg (6.5 mg of PO once weekly, up to maxi adult dose of mg of ba5... prevention of malaria in areas with mainly P vivax 0.5 mg of base/kg (0.8 mg o kg) PO qd, up to adult dose; be taken with food 30 mg of base (52.6 mg of salt) PO qd Used for presumptive 30 mg of base... Blastomycosis can include osteomyelitis in one-fourth of infec­ tions and CNS disease in -40% of pts with AIDS Diagnosis Smears of clinical samples or cultures of sputum, bronchial washings, pus, or tissue