InternalMed_Harrison

InternalMed_Harrison. Patients with advanced HIV disease may develop hyponatremia due to the syndrome of inappropriate antidiuretic hormone (vasopressin) secretion (SIADH) as a consequence of increased free-water intake and decreased free-water excretion. SIADH is usually seen in conjunction with pulmonary or CNS disease. Low serum sodium may also be due to adrenal insufficiency; a concomitant high serum potassium should alert one to this possibility. Hyperkalemia may be secondary to adrenal insufficiency; HIV nephropathy; or medications, particularly trimethoprim and pentamidine. Hypokalemia may be seen in the setting of tenofovir or amphotericin therapy. Adrenal gland disease may be due to mycobacterial infections, CMV disease, cryptococcal disease, histoplasmosis, or ketoconazole toxicity. Iatrogenic Cushing’s syndrome with suppression of the hypothalamic-pituitary-adrenal axis may be seen with the use of local glucocorticoids (injected or inhaled) in patients receiving ritonavir. This is due to


InternalMed_Harrison

InternalMed_Harrison. Cushing’s syndrome with suppression of the hypothalamic-pituitary-adrenal axis may be seen with the use of local glucocorticoids (injected or inhaled) in patients receiving ritonavir. This is due to inhibition of the hepatic enzyme CYP3A4 by ritonavir leading to prolongation of the glucocorticoid half-life.


InternalMed_Harrison

InternalMed_Harrison. Thyroid function may be altered in 10–15% of patients with HIV infection. Both hypoand hyperthyroidism may be seen. The predominant abnormality is subclinical hypothyroidism. In the setting of cART, up to 10% of patients have been noted to have elevated thyroid-stimulating hormone levels, suggesting that this may be


InternalMed_Harrison

InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1260 characterizes HIV infection and reflects the complex nature of the immune system and its regulatory mechanisms. Drug allergies are the most significant allergic reactions occurring in HIV-infected patients and appear to become more common as the disease progresses. They occur in up to 65% of patients who receive therapy with TMP/SMX for PCP. In general, these drug reactions are characterized by erythematous, morbilliform eruptions that are pruritic, tend to coalesce, and are often associated with fever. Nonetheless, ~33% of patients can be maintained on the offending therapy, and thus these reactions are not an immediate indication to stop the drug. Anaphylaxis is extremely rare in patients with HIV infection, and patients who have a cutaneous reaction during a single course of therapy can still be considered candidates for future treatment or prophylaxis with the same agent. The one exception to this is the


InternalMed_Harrison

InternalMed_Harrison. patients who have a cutaneous reaction during a single course of therapy can still be considered candidates for future treatment or prophylaxis with the same agent. The one exception to this is the nucleoside analogue abacavir, where fatal hypersensitivity reactions have been reported with rechallenge. This hypersensitivity is strongly associated with the HLA-B5701 haplotype, and a hypersensitivity reaction to abacavir is an absolute contraindication to future therapy. For other agents, including TMP/SMX, desensitization regimens are moderately successful. While the mechanisms underlying these allergic-type reactions remain unknown, patients with HIV infection have been noted to have elevated IgE levels that increase as the CD4+ T cell count declines. The numerous examples of patients with multiple drug reactions suggest that a common pathway is involved.


InternalMed_Harrison

InternalMed_Harrison. HIV infection shares many similarities with a variety of autoimmune diseases, including a substantial polyclonal B cell activation that is associated with a high incidence of antiphospho lipid antibodies, such as anticardiolipin antibodies, VDRL antibodies, and lupus-like anticoagulants. FIGuRE 226-38 Characteristics of lipodystrophy. A. Truncal obesity and buffalo hump. In addition, HIV-infected individuals have an B. Facial wasting. C. Accumulation of intraabdominal fat on CT scan.


InternalMed_Harrison

InternalMed_Harrison. increased incidence of antinuclear antibodies. Despite these serologic findings, there is no evidence that HIV-infected individuals have an a manifestation of immune reconstitution. Immune-reconstitution increase in two of the more common autoimmune diseases, i.e., Graves’ disease may occur as a late (9–48 months) complication of systemic lupus erythematosus and rheumatoid arthritis. In fact, itcART. In advanced HIV disease, infection of the thyroid gland may has been observed that these diseases may be somewhat ameliorated occur with opportunistic pathogens, including P. jiroveci, CMV, by the concomitant presence of HIV infection, suggesting that an mycobacteria, Toxoplasma gondii, and Cryptococcus neoformans. intact CD4+ T cell limb of the immune response plays an integralThese infections are generally associated with a nontender, diffuse role in the pathogenesis of these conditions. Similarly, there are anecenlargement of the thyroid gland. Thyroid function is usually normal. dotal


InternalMed_Harrison

InternalMed_Harrison. are generally associated with a nontender, diffuse role in the pathogenesis of these conditions. Similarly, there are anecenlargement of the thyroid gland. Thyroid function is usually normal. dotal reports of patients with common variable immunodeficiencyDiagnosis is made by fine-needle aspirate or open biopsy. (Chap. 374), characterized by hypogammaglobulinemia, who haveDepending on the severity of disease, HIV infection is associated had a normalization of Ig levels following the development of HIVwith hypogonadism in 20–50% of men. While this is generally a com-infection, suggesting a possible role for overactive CD4+ T cell plication of underlying illness, testicular dysfunction may also be a immunity in certain forms of that syndrome. The one autoimmuneside effect of ganciclovir therapy. In some surveys, up to two-thirds disease that may occur with an increased frequency in patientsof patients report decreased libido and one-third complain of erectile with HIV infection is a


InternalMed_Harrison

InternalMed_Harrison. therapy. In some surveys, up to two-thirds disease that may occur with an increased frequency in patientsof patients report decreased libido and one-third complain of erectile with HIV infection is a variant of primary Sjögren’s syndromedysfunction. Androgen-replacement therapy should be considered in (Chap. 383). Patients with HIV infection may develop a syndromepatients with symptomatic hypogonadism. HIV infection does not consisting of parotid gland enlargement, dry eyes, and dry mouthseem to have a significant effect on the menstrual cycle outside the that is associated with lymphocytic infiltrates of the salivary glandsetting of advanced disease. and lung. One also can see peripheral neuropathy, polymyositis, renal tubular acidosis, and hepatitis. In contrast to Sjögren’s syndrome, Immunologic and Rheumatologic Diseases Immunologic and rheumato-in which the lymphocytic infiltrates are composed predominantly logic disorders are common in patients with HIV infection and range of


InternalMed_Harrison

InternalMed_Harrison. Immunologic and Rheumatologic Diseases Immunologic and rheumato-in which the lymphocytic infiltrates are composed predominantly logic disorders are common in patients with HIV infection and range of CD4+ T cells, in patients with HIV infection the infiltrates are from excessive immediate-type hypersensitivity reactions (Chap. 376) composed predominantly of CD8+ T cells. In addition, while patients to an increase in the incidence of reactive arthritis (Chap. 384) to with Sjögren’s syndrome are mainly women who have autoantibodconditions characterized by a diffuse infiltrative lymphocytosis. The ies to Ro and La and who frequently have HLA-DR3 or -B8 MHC occurrence of these phenomena is an apparent paradox in the setting haplotypes, HIV-infected individuals with this syndrome are usually of the profound immunodeficiency and immunosuppression that African-American men who do not have anti-Ro or anti-La and who most often are HLA-DR5. This syndrome appears to be less common with the


InternalMed_Harrison

InternalMed_Harrison. of the profound immunodeficiency and immunosuppression that African-American men who do not have anti-Ro or anti-La and who most often are HLA-DR5. This syndrome appears to be less common with the increased use of effective cART. The term diffuse infiltrative lymphocytosis syndrome (DILS) is used to describe this entity and to distinguish it from Sjögren’s syndrome.


InternalMed_Harrison

InternalMed_Harrison. Approximately one-third of HIV-infected individuals experience arthralgias; furthermore, 5–10% are diagnosed as having some form of reactive arthritis, such as Reiter’s syndrome or psoriatic arthritis as well as undifferentiated spondyloarthropathy (Chap. 384). These syndromes occur with increasing frequency as the competency of the immune system declines. This association may be related to an increase in the number of infections with organisms that may trigger a reactive arthritis with progressive immunodeficiency or to a loss of important regulatory T cells. Reactive arthritides in HIV-infected individuals generally respond well to standard treatment; however, therapy with methotrexate has been associated with an increase in the incidence of opportunistic infections and should be used with caution and only in severe cases.


InternalMed_Harrison

InternalMed_Harrison. HIV-infected individuals also experience a variety of joint problems without obvious cause that are referred to generically as HIVor AIDS-associated arthropathy. This syndrome is characterized by sub-acute oligoarticular arthritis developing over a period of 1–6 weeks and lasting 6 weeks to 6 months. It generally involves the large joints, predominantly the knees and ankles, and is nonerosive with only a mild inflammatory response. X-rays are nonrevealing. Nonsteroidal anti-inflammatory drugs are only marginally helpful; however, relief has been noted with the use of intraarticular glucocorticoids. A second form of arthritis also thought to be secondary to HIV infection is called painful articular syndrome. This condition, reported as occurring in as many as 10% of AIDS patients, presents as an acute, severe, sharp pain in the affected joint. It affects primarily the knees, elbows, and shoulders; lasts 2–24 h; and may be severe enough to require narcotic analgesics. The cause of this


InternalMed_Harrison

InternalMed_Harrison. as an acute, severe, sharp pain in the affected joint. It affects primarily the knees, elbows, and shoulders; lasts 2–24 h; and may be severe enough to require narcotic analgesics. The cause of this arthropathy is unclear; however, it is thought to result from a direct effect of HIV on the joint. This condition is reminiscent of the fact that other lentiviruses, in particular the caprine arthritis-encephalitis virus, are capable of directly causing arthritis.


InternalMed_Harrison

InternalMed_Harrison. A variety of other immunologic or rheumatologic diseases have been reported in HIV-infected individuals, either de novo or in association with opportunistic infections or drugs. Using the criteria of widespread musculoskeletal pain of at least 3 months’ duration and the presence of at least 11 of 18 possible tender points by digital palpation, 11% of an HIV-infected cohort containing 55% IDUs were diagnosed as having fibromyalgia (Chap. 396). While the incidence of frank arthritis was less in this population than in other studied populations that consisted predominantly of men who have sex with men, these data support the concept that there are musculoskeletal problems that occur as a direct result of HIV infection. In addition there have been reports of leukocytoclastic vasculitis in the setting of zidovudine therapy. CNS angiitis and polymyositis also have been reported in HIV-infected individuals. Septic arthritis is surprisingly rare, especially given the increased incidence of


InternalMed_Harrison

InternalMed_Harrison. setting of zidovudine therapy. CNS angiitis and polymyositis also have been reported in HIV-infected individuals. Septic arthritis is surprisingly rare, especially given the increased incidence of staphylococcal bacteremias seen in this population. When septic arthritis has been reported, it has usually been due to Staphylococcus aureus, systemic fungal infection with


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InternalMed_Harrison. C. neoformans, Sporothrix schenckii, or H. capsulatum or to systemic mycobacterial infection with M. tuberculosis, M. haemophilum, M. avium, or M. kansasii.


InternalMed_Harrison

InternalMed_Harrison. Patients with HIV infection treated with cART have been found to have an increased incidence of osteonecrosis or avascular necrosis of the hip and shoulders. In a study of asymptomatic patients, 4.4% were found to have evidence of osteonecrosis on MRI. While precise causeand-effect relationships have been difficult to establish, this complication has been associated with the use of lipid-lowering agents, systemic glucocorticoids, and testosterone; bodybuilding exercise; alcohol consumption; and the presence of anticardiolipin antibodies. Osteoporosis has been reported in 7% of women with HIV infection, with 41% of women demonstrating some degree of osteopenia. Several studies have documented decreases in bone mineral density of 2–6% in the first 2 years following the initiation of cART. This may be particularly apparent with tenofovir-containing regimens.


InternalMed_Harrison

InternalMed_Harrison. worsening of an existing clinical condition or abrupt appearance of a new clinical finding (unmasking) is seen following the initiation of antiretroviral therapy weeks to months following the initiation of antiretroviral therapy most common in patients starting therapy with a CD4+ T cell count • Is frequently seen in the setting of tuberculosis; particularly when cART is starting soon after initiation of anti-TB therapy


InternalMed_Harrison

InternalMed_Harrison. Following the initiation of effective cART, a paradoxical worsening of preexisting, untreated, or partially treated opportunistic infections may be noted. One may also see exacerbations of pre-existing or the development of new autoimmune conditions following the initiation of antiretrovirals (Table 226-12). IRIS related to a known pre-existing infection or neoplasm is referred to as paradoxical IRIS, while IRIS associated with a previously undiagnosed condition is referred to as unmasking IRIS. The term immune reconstitution disease (IRD) is sometimes used to distinguish IRIS manifestations related to opportunistic diseases from IRIS manifestations related to autoimmune diseases. IRD is particularly common in patients with underlying untreated mycobacterial or fungal infections. IRIS is seen in 10–30% of patients, depending on the clinical setting, and is most common in patients starting therapy with CD4+ T cell counts <50 cells/μL who have a precipitous drop in HIV RNA levels


InternalMed_Harrison

InternalMed_Harrison. is seen in 10–30% of patients, depending on the clinical setting, and is most common in patients starting therapy with CD4+ T cell counts <50 cells/μL who have a precipitous drop in HIV RNA levels following the initiation of cART. Signs and symptoms may appear anywhere from 2 weeks to 2 years after the initiation of cART and can include localized lymphadenitis, prolonged fever, pulmonary infiltrates, hepatitis, increased intracranial pressure, uveitis, sarcoidosis, and Graves’ disease. The clinical course can be protracted, and severe cases can be fatal. The underlying mechanism appears to be related to a phenomenon similar to type IV hypersensitivity reactions and reflects the immediate improvements in immune function that occur as levels of HIV RNA drop and the immunosuppressive effects of HIV infection are controlled. In severe cases, the use of immunosuppressive drugs such as glucocorticoids may be required to blunt the inflammatory component of these reactions while specific


InternalMed_Harrison

InternalMed_Harrison. of HIV infection are controlled. In severe cases, the use of immunosuppressive drugs such as glucocorticoids may be required to blunt the inflammatory component of these reactions while specific antimicrobial therapy takes effect.


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InternalMed_Harrison. Diseases of the Hematopoietic System Disorders of the hematopoietic system including lymphadenopathy, anemia, leukopenia, and/or thrombocytopenia are common throughout the course of HIV infection and may be the direct result of HIV, manifestations of secondary infections and neoplasms, or side effects of therapy (Table 226-13). Direct histologic examination and culture of lymph node or bone marrow tissue are often diagnostic. A significant percentage of bone marrow aspirates from patients with HIV infection have been reported to contain lymphoid aggregates, the precise significance of which is unknown. Initiation of cART will lead to reversal of most hematologic complications that are the direct result of HIV infection.


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1262 Some patients, otherwise asymptomatic, may develop persistent generalized lymphadenopathy as an early clinical manifestation of HIV infection. This condition is defined as the presence of enlarged lymph nodes (>1 cm) in two or more extrainguinal sites for >3 months without an obvious cause. The lymphadenopathy is due to marked follicular hyperplasia in the node in response to HIV infection. The nodes are generally discrete and freely movable. This feature of HIV disease may be seen at any point in the spectrum of immune dysfunction and is not associated with an increased likelihood of developing AIDS. Paradoxically, a loss in lymphadenopathy or a decrease in lymph node size outside the setting of cART may be a prognostic marker of disease progression. In patients with CD4+ T cell counts >200/ μL, the differential diagnosis of lymphadenopathy includes KS, TB, Castleman’s disease, and lymphoma. In patients with more


InternalMed_Harrison

InternalMed_Harrison. marker of disease progression. In patients with CD4+ T cell counts >200/ μL, the differential diagnosis of lymphadenopathy includes KS, TB, Castleman’s disease, and lymphoma. In patients with more advanced disease, lymphadenopathy may also be due to atypical mycobacterial infection, toxoplasmosis, systemic fungal infection, or bacillary angiomatosis. While indicated in patients with CD4+ T cell counts <200/μL, lymph node biopsy is not indicated in patients with early-stage disease unless there are signs and symptoms of systemic illness, such as fever and weight loss, or unless the nodes begin to enlarge, become fixed, or coalesce. Monoclonal gammopathy of unknown significance (MGUS) (Chap. 136), defined as the presence of a serum monoclonal IgG, IgA, or IgM in the absence of a clear cause, has been reported in 3% of patients with HIV infection. The overall clinical significance of this finding in patients with HIV infection is unclear, although it has been associated with other viral


InternalMed_Harrison

InternalMed_Harrison. has been reported in 3% of patients with HIV infection. The overall clinical significance of this finding in patients with HIV infection is unclear, although it has been associated with other viral infections, non-Hodgkin’s lymphoma, and plasma cell malignancy. Anemia is the most common hematologic abnormality in HIV-infected patients and, in the absence of a specific treatable cause, is independently associated with a poor prognosis. While generally mild, anemia can be quite severe and require chronic blood transfusions. Among the specific reversible causes of anemia in the setting of HIV infection are drug toxicity, systemic fungal and mycobacterial infections, nutritional deficiencies, and parvovirus B19 infections. Zidovudine may block erythroid maturation prior to its effects on other marrow elements. A characteristic feature of zidovudine therapy is an elevated mean corpuscular volume (MCV). Another drug used in patients with HIV infection that has a selective effect on the


InternalMed_Harrison

InternalMed_Harrison. other marrow elements. A characteristic feature of zidovudine therapy is an elevated mean corpuscular volume (MCV). Another drug used in patients with HIV infection that has a selective effect on the erythroid series is dapsone. This drug can cause a serious hemolytic anemia in patients who are deficient in glucose-6-phosphate dehydrogenase and can create a functional anemia in others through induction of methemoglobinemia. Folate levels are usually normal in HIV-infected individuals; however, vitamin B12 levels may be depressed as a consequence of achlorhydria or malabsorption. True autoimmune hemolytic anemia is rare, although ~20% of patients with HIV infection may have a positive direct antiglobulin test as a consequence of polyclonal B cell activation. Infection with parvovirus B19 may also cause anemia. It is important to recognize this possibility given the fact that it responds well to treatment with IVIg. Erythropoietin levels in patients with HIV infection and anemia are


InternalMed_Harrison

InternalMed_Harrison. may also cause anemia. It is important to recognize this possibility given the fact that it responds well to treatment with IVIg. Erythropoietin levels in patients with HIV infection and anemia are generally lower than expected given the degree of anemia. Treatment with erythropoietin may result in an increase in hemoglobin levels. An exception to this is a subset of patients with zidovudine-associated anemia in whom erythropoietin levels may be quite high. During the course of HIV infection, neutropenia may be seen in approximately half of patients. In most instances it is mild; however, it can be severe and can put patients at risk of spontaneous bacterial infections. This is most frequently seen in patients with severely advanced HIV disease and in patients receiving any of a number of potentially myelosuppressive therapies. In the setting of neutropenia, diseases that are not commonly seen in HIV-infected patients, such as aspergillosis or mucormycosis, may occur. Both granulocyte


InternalMed_Harrison

InternalMed_Harrison. potentially myelosuppressive therapies. In the setting of neutropenia, diseases that are not commonly seen in HIV-infected patients, such as aspergillosis or mucormycosis, may occur. Both granulocyte colony-stimulating factor (G-CSF) and GM-CSF increase neutrophil counts in patients with HIV infection regardless of the cause of the neutropenia. Earlier concerns about the potential of these agents to also increase levels of HIV were not confirmed in controlled clinical trials. Thrombocytopenia may be an early consequence of HIV infection. Approximately 3% of patients with untreated HIV infection and CD4+ T cell counts ≥400/μL have platelet counts <150,000/μL. For untreated patients with CD4+ T cell counts <400/μL, this incidence increases to 10%. In patients receiving antiretrovirals, thrombocytopenia is associated with hepatitis C, cirrhosis, and ongoing high-level HIV replication. Thrombocytopenia is rarely a serious clinical problem in patients with HIV infection and generally


InternalMed_Harrison

InternalMed_Harrison. thrombocytopenia is associated with hepatitis C, cirrhosis, and ongoing high-level HIV replication. Thrombocytopenia is rarely a serious clinical problem in patients with HIV infection and generally responds well to successful cART. Clinically, it resembles the thrombocytopenia seen in patients with idiopathic thrombocytopenic purpura (Chap. 140). Immune complexes containing anti-gp120 antibodies and anti-anti-gp120 antibodies have been noted in the circulation and on the surface of platelets in patients with HIV infection. Patients with HIV infection have also been noted to have a platelet-specific antibody directed toward a 25-kDa component of the surface of the platelet. Other data suggest that the thrombocytopenia in patients with HIV infection may be due to a direct effect of HIV on megakaryocytes. Whatever the cause, it is very clear that the most effective medical approach to this problem has been the use of cART. For patients with platelet counts <20,000/μL, a more aggressive


InternalMed_Harrison

InternalMed_Harrison. megakaryocytes. Whatever the cause, it is very clear that the most effective medical approach to this problem has been the use of cART. For patients with platelet counts <20,000/μL, a more aggressive approach combining IVIg or anti-Rh Ig for an immediate response and cART for a more lasting response is appropriate. Rituximab has been used with some success in otherwise refractory cases. Splenectomy is a rarely needed option and is reserved for patients refractory to medical management. Because of the risk of serious infection with encapsulated organisms, all patients with HIV infection about to undergo splenectomy should be immunized with pneumococcal polysaccharide. It should be noted that, in addition to causing an increase in the platelet count, removal of the spleen will result in an increase in the peripheral blood lymphocyte count, making CD4+ T cell counts unreliable markers of immunocompetence. In this setting, the clinician should rely on the CD4+ T cell percentage for making


InternalMed_Harrison

InternalMed_Harrison. in the peripheral blood lymphocyte count, making CD4+ T cell counts unreliable markers of immunocompetence. In this setting, the clinician should rely on the CD4+ T cell percentage for making diagnostic decisions with respect to the likelihood of opportunistic infections. A CD4+ T cell percentage of 15 is approximately equivalent to a CD4+ T cell count of 200/μL. In patients with early HIV infection, thrombocytopenia has also been reported as a consequence of classic thrombotic thrombocytopenic purpura (Chap. 140). This clinical syndrome, consisting of fever, thrombocytopenia, hemolytic anemia, and neurologic and renal dysfunction, is a rare complication of early HIV infection. As in other settings, the appropriate management is the use of salicylates and plasma exchange. Other causes of thrombocytopenia include lymphoma, mycobacterial infections, and fungal infections.


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InternalMed_Harrison. The incidence of venous thromboembolic disease such as deep-vein thrombosis or pulmonary embolus is approximately 1% per year in patients with HIV infection. This is approximately 10 times higher than that seen in an age-matched population. Factors associated with an increased risk of clinical thrombosis include age over 45, history of an opportunistic infection, lower CD4 count, and estrogen use. Abnormalities of the coagulation cascade including decreased protein S activity, increases in factor VIII, anticardiolipin antibodies, or lupus-like anticoagulant have been reported in more than 50% of patients with HIV infection. The clinical significance of this increased propensity toward thromboembolic disease is likely reflected in the observation that elevations in d-dimer are strongly associated with all-cause mortality in patients with HIV infection (Table 226-9).


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InternalMed_Harrison. Dermatologic Diseases Dermatologic problems occur in >90% of patients with HIV infection. From the macular, roseola-like rash seen with the acute seroconversion syndrome to extensive end-stage KS, cutaneous manifestations of HIV disease can be seen throughout the course of HIV infection. Among the more common nonneoplastic problems are seborrheic dermatitis, folliculitis, and opportunistic infections. Extrapulmonary pneumocystosis may cause a necrotizing vasculitis. Neoplastic conditions are covered below. Seborrheic dermatitis occurs in 3% of the general population and in up to 50% of patients with HIV infection. Seborrheic dermatitis increases in prevalence and severity as the CD4+ T cell count declines. In HIV-infected patients, seborrheic dermatitis may be aggravated by concomitant infection with Pityrosporum, a yeastlike fungus; use of topical antifungal agents has been recommended in cases refractory to standard topical treatment.


InternalMed_Harrison

InternalMed_Harrison. Folliculitis is among the most prevalent dermatologic disorders in patients with HIV infection and is seen in ~20% of patients. It is more common in patients with CD4+ T cell counts <200 cells/μL. Pruritic papular eruption is one of the most common pruritic rashes in patients with HIV infection. It appears as multiple papules on the face, trunk, and extensor surfaces and may improve with cART. Eosinophilic pustular folliculitis is a rare form of folliculitis that is seen with increased frequency in patients with HIV infection. It presents as multiple, urticarial perifollicular papules that may coalesce into plaquelike lesions. Skin biopsy reveals an eosinophilic infiltrate of the hair follicle, which in certain cases has been associated with the presence of a mite. Patients typically have an elevated serum IgE level and may respond to treatment with topical anthelmintics. Pruritus is a common symptom in patients with HIV infection and can lead to prurigo nodularis. Patients with HIV


InternalMed_Harrison

InternalMed_Harrison. an elevated serum IgE level and may respond to treatment with topical anthelmintics. Pruritus is a common symptom in patients with HIV infection and can lead to prurigo nodularis. Patients with HIV infection have also been reported to develop a severe form of Norwegian scabies with hyperkeratotic psoriasiform lesions.


InternalMed_Harrison

InternalMed_Harrison. Both psoriasis and ichthyosis, although they are not reported to be increased in frequency, may be particularly severe when they occur in patients with HIV infection. Preexisting psoriasis may become guttate in appearance and more refractory to treatment in the setting of HIV infection.


InternalMed_Harrison

InternalMed_Harrison. Reactivation herpes zoster (shingles) is seen in 10–20% of patients with HIV infection. This reactivation syndrome of varicella-zoster virus indicates a modest decline in immune function and may be the first indication of clinical immunodeficiency. In one series, patients who developed shingles did so an average of 5 years after HIV infection. In a cohort of patients with HIV infection and localized zoster, the subsequent rate of the development of AIDS was 1% per month. In that study, AIDS was more likely to develop if the outbreak of zoster was associated with severe pain, extensive skin involvement, or involvement of cranial or cervical dermatomes. The clinical manifestations of reactivation zoster in HIV-infected patients, although indicative of immunologic compromise, are not as severe as those seen in other immunodeficient conditions. Thus, while lesions may extend over several dermatomes, involve the spinal cord, and/or be associated with frank cutaneous dissemination, visceral


InternalMed_Harrison

InternalMed_Harrison. as those seen in other immunodeficient conditions. Thus, while lesions may extend over several dermatomes, involve the spinal cord, and/or be associated with frank cutaneous dissemination, visceral involvement has not been reported. In contrast to patients without a known underlying immunodeficiency state, patients with HIV infection tend to have recurrences of zoster with a relapse rate of ~20%. Valacyclovir, acyclovir, or famciclovir is the treatment of choice. Foscarnet may be of value in patients with acyclovir-resistant virus.


InternalMed_Harrison

InternalMed_Harrison. Infection with herpes simplex virus in HIV-infected individuals is associated with recurrent orolabial, genital, and perianal lesions as part of recurrent reactivation syndromes (Chap. 216). As HIV disease progresses and the CD4+ T cell count declines, these infections become more frequent and severe. Lesions often appear as beefy red, are exquisitely painful, and have a tendency to occur high in the gluteal cleft (Fig. 226-37). Perirectal HSV may be associated with proctitis and anal fissures. HSV should be high in the differential diagnosis of any HIV-infected patient with a poorly healing, painful perirectal lesion. In addition to recurrent mucosal ulcers, recurrent HSV infection in the form of herpetic whitlow can be a problem in patients with HIV infection, presenting with painful vesicles or extensive cutaneous erosion. Valacyclovir, acyclovir or famciclovir is the treatment of choice in these settings. It is noteworthy that even subclinical reactivation of herpes simplex may be


InternalMed_Harrison

InternalMed_Harrison. or extensive cutaneous erosion. Valacyclovir, acyclovir or famciclovir is the treatment of choice in these settings. It is noteworthy that even subclinical reactivation of herpes simplex may be associated with increases in plasma HIV RNA levels.


InternalMed_Harrison

InternalMed_Harrison. Diffuse skin eruptions due to Molluscum contagiosum may be seen in patients with advanced HIV infection. These flesh-colored, umbilicated lesions may be treated with local therapy. They tend to regress with effective cART. Similarly, condyloma acuminatum lesions may be more severe and more widely distributed in patients with low CD4+ T cell counts. Imiquimod cream may be helpful in some cases. Atypical mycobacterial infections may present as erythematous cutaneous nodules, as may fungal infections, Bartonella, Acanthamoeba, and KS. Cutaneous infections with Aspergillus have been noted at the site of IV catheter placement.


InternalMed_Harrison

InternalMed_Harrison. The skin of patients with HIV infection is often a target organ for drug reactions (Chap. 74). Although most skin reactions are mild and not necessarily an indication to discontinue therapy, patients may have particularly severe cutaneous reactions, including erythroderma, 1263 Stevens-Johnson syndrome, and toxic epidermal necrolysis, as a reaction to drugs—particularly sulfa drugs, nonnucleoside reverse transcriptase inhibitors, abacavir, amprenavir, darunavir, fosamprenavir, and tipranavir. Similarly, patients with HIV infection are often quite photosensitive and burn easily following exposure to sunlight or as a side effect of radiation therapy (Chap. 75).


InternalMed_Harrison

InternalMed_Harrison. HIV infection and its treatment may be accompanied by cosmetic changes of the skin that are not of great clinical importance but may be troubling to patients. Yellowing of the nails and straightening of the hair, particularly in African-American patients, have been reported as a consequence of HIV infection. Zidovudine therapy has been associated with elongation of the eyelashes and the development of a bluish discoloration to the nails, again more common in African-American patients. Therapy with clofazimine may cause a yellow-orange discoloration of the skin and urine.


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InternalMed_Harrison. Neurologic Diseases Clinical disease of the nervous system accounts for a significant degree of morbidity in a high percentage of patients with HIV infection (Table 226-14). The neurologic problems that occur in HIV-infected individuals may be either primary to the pathogenic processes of HIV infection or secondary to opportunistic infections or neoplasms. Among the more frequent opportunistic diseases that involve the CNS are toxoplasmosis, cryptococcosis, progressive multifocal leukoencephalopathy, and primary CNS lymphoma. Other less common problems include mycobacterial infections; syphilis; and infection with CMV, HTLV-1, Trypanosoma cruzi, or Acanthamoeba. Overall, secondary diseases of the CNS have been reported to occur in approximately one-third of patients with AIDS. These data antedate the widespread use of cART, and this frequency is considerably lower in patients receiving effective antiretroviral drugs. Primary processes related to HIV infection of the nervous system are


InternalMed_Harrison

InternalMed_Harrison. the widespread use of cART, and this frequency is considerably lower in patients receiving effective antiretroviral drugs. Primary processes related to HIV infection of the nervous system are reminiscent of those seen with other lentiviruses, such as the Visna-Maedi virus of sheep.


InternalMed_Harrison

InternalMed_Harrison. Neurologic problems directly attributable to HIV occur throughout the course of infection and may be inflammatory, demyelinating, or degenerative in nature. The term HIV-associated neurocognitive disorders (HAND) is used to describe a spectrum of disorders that range from asymptomatic neurocognitive impairment (ANI) to minor neurocognitive disorder (MND) to clinically severe dementia. The most severe form, HIV-associated dementia (HAD), also referred to as the AIDS dementia complex, or HIV encephalopathy, is considered an AIDS-defining illness. Most HIV-infected patients have some neurologic problem during the course of their disease. Even in the setting of suppressive cART, approximately 50% of HIV-infected individuals can be shown to have mild to moderate neurocognitive impairment using sensitive neuropsychiatric testing. As noted in the section on Cryptococcosis HIV-associated neurocognitive disorders (HAND), including HIV encepha-


InternalMed_Harrison

InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1264 pathogenesis, damage to the CNS may be a direct result of viral infection of the CNS macrophages or glial cells or may be secondary to the release of neurotoxins and potentially toxic cytokines such as IL-1β, TNF-α, IL-6, and TGF-β. It has been reported that HIV-infected individuals with the E4 allele for apoE are at increased risk for AIDS encephalopathy and peripheral neuropathy. Virtually all patients with HIV infection have some degree of nervous system involvement with the virus. This is evidenced by the fact that CSF findings are abnormal in ~90% of patients, even during the asymptomatic phase of HIV infection. CSF abnormalities include pleocytosis (50–65% of patients), detection of viral RNA (~75%), elevated CSF protein (35%), and evidence of intrathecal synthesis of anti-HIV antibodies (90%). It is important to point out that evidence of infection of the CNS with HIV does not imply impairment of cognitive


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InternalMed_Harrison. protein (35%), and evidence of intrathecal synthesis of anti-HIV antibodies (90%). It is important to point out that evidence of infection of the CNS with HIV does not imply impairment of cognitive function. The neurologic function of an HIV-infected individual should be considered normal unless clinical signs and symptoms suggest otherwise. Aseptic meningitis may be seen in any but the very late stages of HIV infection. In the setting of acute primary infection, patients may experience a syndrome of headache, photophobia, and meningismus. Rarely, an acute encephalopathy due to encephalitis may occur. Cranial nerve involvement may be seen, predominantly cranial nerve VII but occasionally V and/or VIII. CSF findings include a lymphocytic pleocytosis, elevated protein level, and normal glucose level. This syndrome, which cannot be clinically differentiated from other viral meningitides (Chap. 165), usually resolves spontaneously within 2–4 weeks; however, in some patients, signs and


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InternalMed_Harrison. level. This syndrome, which cannot be clinically differentiated from other viral meningitides (Chap. 165), usually resolves spontaneously within 2–4 weeks; however, in some patients, signs and symptoms may become chronic. Aseptic meningitis may occur any time in the course of HIV infection; however, it is rare following the development of AIDS. This suggests that clinical aseptic meningitis in the context of HIV infection is an immune-mediated disease. Cryptococcus is the leading infectious cause of meningitis in patients with AIDS (Chap. 239). While the vast majority of these are due to C. neoformans, up to 12% may be due to C. gattii. Cryptococcal meningitis is the initial AIDS-defining illness in ~2% of patients and generally occurs in patients with CD4+ T cell counts <100/μL. Cryptococcal meningitis is particularly common in untreated patients with AIDS in Africa, occurring in ~5% of patients. Most patients present with a picture of subacute meningoencephalitis with fever, nausea,


InternalMed_Harrison

InternalMed_Harrison. meningitis is particularly common in untreated patients with AIDS in Africa, occurring in ~5% of patients. Most patients present with a picture of subacute meningoencephalitis with fever, nausea, vomiting, altered mental status, headache, and meningeal signs. The incidence of seizures and focal neurologic deficits is low. The CSF profile may be normal or may show only modest elevations in WBC or protein levels and decreases in glucose. The opening pressure in the CSF is usually elevated. In addition to meningitis, patients may develop cryptococcomas and cranial nerve involvement. Approximately one-third of patients also have pulmonary disease. Uncommon manifestations of cryptococcal infection include skin lesions that resemble molluscum contagiosum, lymphadenopathy, palatal and glossal ulcers, arthritis, gastroenteritis, myocarditis, and prostatitis. The prostate gland may serve as a reservoir for smoldering cryptococcal infection. The diagnosis of cryptococcal meningitis is made by


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InternalMed_Harrison. arthritis, gastroenteritis, myocarditis, and prostatitis. The prostate gland may serve as a reservoir for smoldering cryptococcal infection. The diagnosis of cryptococcal meningitis is made by identification of organisms in spinal fluid with india ink examination or by the detection of cryptococcal antigen. Blood cultures for fungus are often positive. A biopsy may be needed to make a diagnosis of CNS cryptococcoma. Treatment is with IV amphotericin B 0.7 mg/kg daily, or liposomal amphotericin 4–6 mg/kg daily, with flucytosine 25 mg/kg qid for at least 2 weeks if possible, continuing with amphotericin alone ideally until the CSF culture turns negative. Decreases in renal function in association with amphotericin can lead to increases in flucytosine levels and subsequent bone marrow suppression. Amphotericin is followed by fluconazole 400 mg/d PO for 8 weeks, and then fluconazole 200 mg/d until the CD4+ T cell count has increased to >200 cells/μL for 6 months in response to cART.


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InternalMed_Harrison. Amphotericin is followed by fluconazole 400 mg/d PO for 8 weeks, and then fluconazole 200 mg/d until the CD4+ T cell count has increased to >200 cells/μL for 6 months in response to cART. Repeated lumbar puncture may be required to manage increased intracranial pressure. Symptoms may recur with initiation of cART as an immune reconstitution syndrome (see above). Other fungi that may cause meningitis in patients with HIV infection are C. immitis and H. capsulatum. Meningoencephalitis has also been reported due to Acanthamoeba or Naegleria. HIV-associated dementia consists of a constellation of signs and symptoms of CNS disease. While this is generally a late complication of HIV infection that progresses slowly over months, it can be seen in patients with CD4+ T cell counts >350 cells/μL. A major feature of this entity is the development of dementia, defined as a decline in cognitive ability from a previous level. It may present as impaired ability to concentrate, increased


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InternalMed_Harrison. cells/μL. A major feature of this entity is the development of dementia, defined as a decline in cognitive ability from a previous level. It may present as impaired ability to concentrate, increased forgetfulness, difficulty reading, or increased difficulty performing complex tasks. Initially these symptoms may be indistinguishable from findings of situational depression or fatigue. In contrast to “cortical” dementia (such as Alzheimer’s disease), aphasia, apraxia, and agnosia are uncommon, leading some investigators to classify HIV encephalopathy as a “subcortical dementia” characterized by defects in short-term memory and executive function (see below). In addition to dementia, patients with HIV encephalopathy may also have motor and behavioral abnormalities. Among the motor problems are unsteady gait, poor balance, tremor, and difficulty with rapid alternating movements. Increased tone and deep tendon reflexes may be found in patients with spinal cord involvement. Late stages may


InternalMed_Harrison

InternalMed_Harrison. unsteady gait, poor balance, tremor, and difficulty with rapid alternating movements. Increased tone and deep tendon reflexes may be found in patients with spinal cord involvement. Late stages may be complicated by bowel and/or bladder incontinence. Behavioral problems include apathy, irritability, and lack of initiative, with progression to a vegetative state in some instances. Some patients develop a state of agitation or mild mania. These changes usually occur without significant changes in level of alertness. This is in contrast to the finding of somnolence in patients with dementia due to toxic/metabolic encephalopathies.


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InternalMed_Harrison. HIV-associated dementia is the initial AIDS-defining illness in ~3% of patients with HIV infection and thus only rarely precedes clinical evidence of immunodeficiency. Clinically significant encephalopathy eventually develops in ~25% of untreated patients with AIDS. As immunologic function declines, the risk and severity of HIV-associated dementia increases. Autopsy series suggest that 80–90% of patients with HIV infection have histologic evidence of CNS involvement. Several classification schemes have been developed for grading HIV encephalopathy; a commonly used clinical staging system is outlined in Table 226-15.


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InternalMed_Harrison. The precise cause of HIV-associated dementia remains unclear, although the condition is thought to be a result of a combination of direct effects of HIV on the CNS and associated immune activation. HIV has been found in the brains of patients with HIV encephalopathy by Southern blot, in situ hybridization, PCR, and electron microscopy. Multinucleated giant cells, macrophages, and microglial cells appear to be the main cell types harboring virus in the CNS. Histologically, the major changes are seen in the subcortical areas of the brain and include pallor and gliosis, multinucleated giant cell encephalitis, and vacuolar myelopathy. Less commonly, diffuse or focal spongiform changes occur in the white matter. Areas of the brain involved in motor function, language, and judgment are most severely affected.


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InternalMed_Harrison. There are no specific criteria for a diagnosis of HIV-associated dementia, and this syndrome must be differentiated from a number of other diseases that affect the CNS of HIV-infected patients (Table 226-14). The diagnosis of dementia depends on demonstrating a decline in Asymptomatic 1 SD below mean in No impairments in 2 cognitive domains activities of daily living Mild neurocognitive 1 SD below mean in Impairments in activities disorder 2 cognitive domains of daily living


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InternalMed_Harrison. Mild neurocognitive 1 SD below mean in Impairments in activities disorder 2 cognitive domains of daily living HIV-associated 2 SD below mean in Notable impairments in dementia 2 cognitive domains activities of daily living aNeurocognitive testing should include assessment of at least 5 domains, including attention-information processing, language, abstraction-executive, complex perceptual motor skills, memory (including learning and recall), simple motor skills, or sensory perceptual skills. Appropriate norms must be available to establish the number of domains in which performance is below 1 SD. bFunctional status is typically assessed by self-reporting but might be corroborated by a collateral source. No agreed measures exist for HIV-associated neurocognitive disorder criteria. Note that, for diagnosis of HIV-associated neurocognitive disorder, other causes of dementia must be ruled out and potential confounding effects of substance use or psychiatric illness should be considered.


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InternalMed_Harrison. Source: Adapted from A Antinori et al: Neurology 69:1789, 2007. FIGuRE 226-39 AIDS dementia complex. Postcontrast CT scan through the lateral ventricles of a 47-year-old man with AIDS, altered mental status, and dementia. The lateral and third ventricles and the cerebral sulci are abnormally prominent. Mild white matter hypodensity is seen adjacent to the frontal horns of the lateral ventricles.


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InternalMed_Harrison. cognitive function. This can be accomplished objectively with the use of a Mini-Mental Status Examination (MMSE) in patients for whom prior scores are available. For this reason, it is advisable for all patients with a diagnosis of HIV infection to have a baseline MMSE. However, changes in MMSE scores may be absent in patients with mild HIV encephalopathy. Imaging studies of the CNS, by either MRI or CT, often demonstrate evidence of cerebral atrophy (Fig. 226-39). MRI may also reveal small areas of increased density on T2-weighted images. Lumbar puncture is an important element of the evaluation of patients with HIV infection and neurologic abnormalities. It is generally most helpful in ruling out or making a diagnosis of opportunistic infections. In HIV encephalopathy, patients may have the nonspecific findings of an increase in CSF cells and protein level. While HIV RNA can often be detected in the spinal fluid and HIV can be cultured from the CSF, this finding is not specific for


InternalMed_Harrison

InternalMed_Harrison. the nonspecific findings of an increase in CSF cells and protein level. While HIV RNA can often be detected in the spinal fluid and HIV can be cultured from the CSF, this finding is not specific for HIV encephalopathy. There appears to be no correlation between the presence of HIV in the CSF and the presence of HIV encephalopathy. Elevated levels of macrophage chemoattractant protein (MCP-1), β2-microglobulin, neopterin, and quinolinic acid (a metabolite of tryptophan reported to cause CNS injury) have been noted in the CSF of patients with HIV encephalopathy. These findings suggest that these factors as well as inflammatory cytokines may be involved in the pathogenesis of this syndrome.


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InternalMed_Harrison. Combination antiretroviral therapy is of benefit in patients with HIV-associated dementia. Improvement in neuropsychiatric test scores has been noted for both adult and pediatric patients treated with antiretrovirals. The rapid improvement in cognitive function noted with the initiation of cART suggests that at least some component of this problem is quickly reversible, again supporting at least a partial role of soluble mediators in the pathogenesis. It should also be noted that these patients have an increased sensitivity to the side effects of neuroleptic drugs. The use of these drugs for symptomatic treatment is associated with an increased risk of extrapyramidal side effects; therefore, patients with HIV encephalopathy who receive these agents must be monitored carefully. It is felt by many physicians that the decrease in the prevalence of severe cases of HAND brought about by cART has resulted in an increase in the prevalence of milder forms of this disorder.


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InternalMed_Harrison. Seizures may be a consequence of opportunistic infections, neoplasms, or HIV encephalopathy (Table 226-16). The seizure threshold is often lower than normal in patients with advanced HIV infection due in part to the frequent presence of electrolyte abnormalities. Seizures are seen in 15–40% of patients with cerebral toxoplasmosis,


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InternalMed_Harrison. Overall Contribution Fraction of Patients Disease to First Seizure, % Who Have Seizures, % 15–35% of patients with primary CNS lymphoma, 8% of patients with cryptococcal meningitis, and 7–50% of patients with HIV encephalopathy. Seizures may also be seen in patients with CNS tuberculosis, aseptic meningitis, and progressive multifocal leukoencephalopathy. Seizures may be the presenting clinical symptom of HIV disease. In one study of 100 patients with HIV infection presenting with a first seizure, cerebral mass lesions were the most common cause, responsible for 32 of the 100 new-onset seizures. Of these 32 cases, 28 were due to toxoplasmosis and 4 to lymphoma. HIV encephalopathy accounted for an additional 24 new-onset seizures. Cryptococcal meningitis was the third most common diagnosis, responsible for 13 of the 100 seizures. In 23 cases, no cause could be found, and it is possible that these cases represent a subcategory of HIV encephalopathy. Of these 23 cases, 16 (70%) had 2 or


InternalMed_Harrison

InternalMed_Harrison. responsible for 13 of the 100 seizures. In 23 cases, no cause could be found, and it is possible that these cases represent a subcategory of HIV encephalopathy. Of these 23 cases, 16 (70%) had 2 or more seizures, suggesting that anticonvulsant therapy is indicated in all patients with HIV infection and seizures unless a rapidly correctable cause is found. While phenytoin remains the initial treatment of choice, hypersensitivity reactions to this drug have been reported in >10% of patients with AIDS, and therefore the use of phenobarbital or valproic acid should be considered as alternatives. Due to a variety of drug-drug interactions between antiseizure medications and antiretrovirals, drug levels need to be monitored carefully.


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InternalMed_Harrison. Patients with HIV infection may present with focal neurologic deficits from a variety of causes. The most common causes are toxoplasmosis, progressive multifocal leukoencephalopathy, and CNS lymphoma. Other causes include cryptococcal infections (discussed above; also Chap. 239), stroke, and reactivation of Chagas’ disease.


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InternalMed_Harrison. Toxoplasmosis has been one of the most common causes of secondary CNS infections in patients with AIDS, but its incidence is decreasing in the era of cART. It is most common in patients from the Caribbean and from France, where the seroprevalence of T. gondii is around 50%. This figure is closer to 15% in the United States. Toxoplasmosis is generally a late complication of HIV infection and usually occurs in patients with CD4+ T cell counts <200/μL. Cerebral toxoplasmosis is thought to represent a reactivation of latent tissue cysts. It is 10 times more common in patients with antibodies to the organism than in patients who are seronegative. Patients diagnosed with HIV infection should be screened for IgG antibodies to T. gondii during the time of their initial workup. Those who are seronegative should be counseled about ways to minimize the risk of primary infection including avoiding the consumption of undercooked meat and careful hand washing after contact with soil or changing the


InternalMed_Harrison

InternalMed_Harrison. should be counseled about ways to minimize the risk of primary infection including avoiding the consumption of undercooked meat and careful hand washing after contact with soil or changing the cat litter box. The most common clinical presentation of cerebral toxoplasmosis in patients with HIV infection is fever, headache, and focal neurologic deficits. Patients may present with seizure, hemiparesis, or aphasia as a manifestation of these focal deficits or with a picture more influenced by the accompanying cerebral edema and characterized by confusion, dementia, and lethargy, which can progress to coma. The diagnosis is usually suspected on the basis of MRI findings of multiple lesions in multiple locations, although in some cases only a single lesion is seen. Pathologically, these lesions generally exhibit inflammation and central necrosis and, as a result, demonstrate ring enhancement on contrast MRI (Fig. 226-40) or, if MRI is unavailable or contraindicated, on double-dose contrast


InternalMed_Harrison

InternalMed_Harrison. generally exhibit inflammation and central necrosis and, as a result, demonstrate ring enhancement on contrast MRI (Fig. 226-40) or, if MRI is unavailable or contraindicated, on double-dose contrast CT. There is usually evidence of surrounding edema. In addition to toxoplasmosis, the differential diagnosis of single or multiple enhancing mass lesions in


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders FIGuRE 226-40 Central nervous system toxoplasmosis. A coronal postcontrast T1-weighted MRI scan demonstrates a peripheral enhancing lesion in the left frontal lobe, associated with an eccentric nodular area of enhancement (arrow); this so-called eccentric target sign is typical of toxoplasmosis.


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InternalMed_Harrison. the HIV-infected patient includes primary CNS lymphoma and, less commonly, TB or fungal or bacterial abscesses. The definitive diagnostic procedure is brain biopsy. However, given the morbidity rate that can accompany this procedure, it is usually reserved for the patient who has failed 2–4 weeks of empiric therapy for toxoplasmosis. If the patient is seronegative for T. gondii, the likelihood that a mass lesion is due to toxoplasmosis is <10%. In that setting, one may choose to be more aggressive and perform a brain biopsy sooner. Standard treatment is sulfadiazine and pyrimethamine with leucovorin as needed for a minimum of 4–6 weeks. Alternative therapeutic regimens include clindamycin in combination with pyrimethamine; atovaquone plus pyrimethamine; and azithromycin plus pyrimethamine plus rifabutin. Relapses are common, and it is recommended that patients with a history of prior toxoplasmic encephalitis receive maintenance therapy with sulfadiazine, pyrimethamine, and leucovorin


InternalMed_Harrison

InternalMed_Harrison. plus rifabutin. Relapses are common, and it is recommended that patients with a history of prior toxoplasmic encephalitis receive maintenance therapy with sulfadiazine, pyrimethamine, and leucovorin as long as their CD4+ T cell counts remain <200 cells/μL. Patients with CD4+ T cell counts <100/μL and IgG antibody to Toxoplasma should receive primary prophylaxis for toxoplasmosis. Fortunately, the same daily regimen of a single double-strength tablet of TMP/SMX used for P. jiroveci prophylaxis provides adequate primary protection against toxoplasmosis. Secondary prophylaxis/maintenance therapy for toxoplasmosis may be discontinued in the setting of effective cART and increases in CD4+ T cell counts to >200/μL for 6 months.


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InternalMed_Harrison. JC virus, a human polyomavirus that is the etiologic agent of progressive multifocal leukoencephalopathy (PML), is an important opportunistic pathogen in patients with AIDS (Chap. 164). While ~80% of the general adult population has antibodies to JC virus, indicative of prior infection, <10% of healthy adults show any evidence of ongoing viral replication. PML is the only known clinical manifestation of JC virus infection. It is a late manifestation of AIDS and is seen in ~1–4% of patients with AIDS. The lesions of PML begin as small foci of demyelination in subcortical white matter that eventually coalesce. The cerebral hemispheres, cerebellum, and brainstem may all be involved. Patients typically have a protracted course with multifocal neurologic deficits, with or without changes in mental status. Approximately 20% of patients experience seizures. Ataxia, hemiparesis, visual field defects, aphasia, and sensory defects may occur. Headache, fever, nausea, and vomiting are rarely


InternalMed_Harrison

InternalMed_Harrison. mental status. Approximately 20% of patients experience seizures. Ataxia, hemiparesis, visual field defects, aphasia, and sensory defects may occur. Headache, fever, nausea, and vomiting are rarely seen. Their presence should suggest another diagnosis. MRI typically reveals multiple, nonenhancing white matter lesions that may coalesce and have a predilection for the occipital and parietal lobes. The lesions show signal hyperintensity on T2-weighted images and diminished signal on T1-weighted images. The measurement of JC virus DNA levels in CSF has a diagnostic sensitivity of 76% and a specificity of close to 100%. Prior to the availability of cART, the majority of patients with PML died within 3–6 months of the onset of symptoms. Paradoxical worsening of PML has been seen with initiation of cART as an immune reconstitution syndrome. There is no specific treatment for PML; however, a median survival of 2 years and survival of >15 years have been reported in patients with PML treated


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InternalMed_Harrison. of cART as an immune reconstitution syndrome. There is no specific treatment for PML; however, a median survival of 2 years and survival of >15 years have been reported in patients with PML treated with cART for their HIV disease. Despite having a significant impact on survival, only ~50% of patients with HIV infection and PML show neurologic improvement with cART. Studies with other antiviral agents such as cidofovir have failed to show clear benefit. Factors influencing a favorable prognosis for PML in the setting of HIV infection include a CD4+ T cell count >100/μL at baseline and the ability to maintain an HIV viral load of <500 copies/mL. Baseline HIV-1 viral load does not have independent predictive value of survival. PML is one of the few opportunistic infections that continues to occur with some frequency despite the widespread use of cART.


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InternalMed_Harrison. Reactivation American trypanosomiasis may present as acute meningoencephalitis with focal neurologic signs, fever, headache, vomiting, and seizures. Accompanying cardiac disease in the form of arrhythmias or heart failure should increase the index of suspicion. The presence of antibodies to T. cruzi supports the diagnosis. In South America, reactivation of Chagas’ disease is considered to be an AIDS-defining condition and may be the initial AIDS-defining condition. The majority of cases occur in patients with CD4+ T cell counts <200 cells/μL. Lesions appear radiographically as single or multiple hypodense areas, typically with ring enhancement and edema. They are found predominantly in the subcortical areas, a feature that differentiates them from the deeper lesions of toxoplasmosis. T. cruzi amastigotes, or trypanosomes, can be identified from biopsy specimens or CSF. Other CSF findings include elevated protein and a mild (<100 cells/μL) lymphocytic pleocytosis. Organisms can also be


InternalMed_Harrison

InternalMed_Harrison. amastigotes, or trypanosomes, can be identified from biopsy specimens or CSF. Other CSF findings include elevated protein and a mild (<100 cells/μL) lymphocytic pleocytosis. Organisms can also be identified by direct examination of the blood. Treatment consists of benzimidazole (2.5 mg/kg bid) or nifurtimox (2 mg/kg qid) for at least 60 days, followed by maintenance therapy for the duration of immunodeficiency with either drug at a dose of 5 mg/kg three times a week. As is the case with cerebral toxoplasmosis, successful therapy with antiretrovirals may allow discontinuation of therapy for Chagas’ disease.


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InternalMed_Harrison. Stroke may occur in patients with HIV infection. In contrast to the other causes of focal neurologic deficits in patients with HIV infection, the symptoms of a stroke are sudden in onset. Patients with HIV infection have an increased prevalence of many classic risk factors associated with stroke, including smoking and diabetes. It has been reported that HIV infection itself can lead to an increase in carotid artery stiffness. The relative increase in risk for stroke as a consequence of HIV infection is more pronounced in women and in individuals between the ages of 18 and 29. Among the secondary infectious diseases in patients with HIV infection that may be associated with stroke are vasculitis due to cerebral varicella zoster or neurosyphilis and septic embolism in association with fungal infection. Other elements of the differential diagnosis of stroke in the patient with HIV infection include atherosclerotic cerebral vascular disease, thrombotic thrombocytopenic purpura, and


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InternalMed_Harrison. fungal infection. Other elements of the differential diagnosis of stroke in the patient with HIV infection include atherosclerotic cerebral vascular disease, thrombotic thrombocytopenic purpura, and cocaine or amphetamine use.


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InternalMed_Harrison. Primary CNS lymphoma is discussed below in the section on neoplastic diseases.


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InternalMed_Harrison. Spinal cord disease, or myelopathy, is present in ~20% of patients with AIDS, often as part of HIV-associated neurocognitive disorder. In fact, 90% of the patients with HIV-associated myelopathy have some evidence of dementia, suggesting that similar pathologic processes may be responsible for both conditions. Three main types of spinal cord disease are seen in patients with AIDS. The first of these is a vacuolar myelopathy, as mentioned above. This condition is pathologically similar to subacute combined degeneration of the cord, such as that occurring with pernicious anemia. Although vitamin B12 deficiency can be seen in patients with AIDS as a primary complication of HIV infection, it does not appear to be responsible for the myelopathy seen in the majority of patients. Vacuolar myelopathy is characterized by a subacute onset and often presents with gait disturbances, predominantly ataxia and spasticity; it may progress to include bladder and bowel dysfunction. Physical findings


InternalMed_Harrison

InternalMed_Harrison. is characterized by a subacute onset and often presents with gait disturbances, predominantly ataxia and spasticity; it may progress to include bladder and bowel dysfunction. Physical findings include evidence of increased deep tendon reflexes and extensor plantar responses. The second form of spinal cord disease involves the dorsal columns and presents as a pure sensory ataxia. The third form is also sensory in nature and presents with paresthesias and dysesthesias of the lower extremities. In contrast to the cognitive problems seen in patients with HIV encephalopathy, these spinal cord syndromes do not respond well to antiretroviral drugs, and therapy is mainly supportive.


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InternalMed_Harrison. One important disease of the spinal cord that also involves the peripheral nerves is a myelopathy and polyradiculopathy seen in association with CMV infection. This entity is generally seen late in the course of HIV infection and is fulminant in onset, with lower extremity and sacral paresthesias, difficulty in walking, areflexia, ascending sensory loss, and urinary retention. The clinical course is rapidly progressive over a period of weeks. CSF examination reveals a predominantly neutrophilic pleocytosis, and CMV DNA can be detected by CSF PCR. Therapy with ganciclovir or foscarnet can lead to rapid improvement, and prompt initiation of foscarnet or ganciclovir therapy is important in minimizing the degree of permanent neurologic damage. Combination therapy with both drugs should be considered in patients who have been previously treated for CMV disease. Other diseases involving the spinal cord in patients with HIV infection include HTLV-1-associated myelopathy (HAM) (Chap. 225e),


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InternalMed_Harrison. in patients who have been previously treated for CMV disease. Other diseases involving the spinal cord in patients with HIV infection include HTLV-1-associated myelopathy (HAM) (Chap. 225e), neurosyphilis (Chap. 206), infection with herpes simplex (Chap. 216) or varicella-zoster (Chap. 217), TB (Chap. 202), and lymphoma (Chap. 134).


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InternalMed_Harrison. Peripheral neuropathies are common in patients with HIV infection. They occur at all stages of illness and take a variety of forms. Early in the course of HIV infection, an acute inflammatory demyelinating polyneuropathy resembling Guillain-Barré syndrome may occur (Chap. 460). In other patients, a progressive or relapsing-remitting inflammatory neuropathy resembling chronic inflammatory demyelinating polyneuropathy (CIDP) has been noted. Patients commonly present with progressive weakness, areflexia, and minimal sensory changes. CSF examination often reveals a mononuclear pleocytosis, and peripheral nerve biopsy demonstrates a perivascular infiltrate suggesting an autoimmune etiology. Plasma exchange or IVIg has been tried with variable success. Because of the immunosuppressive effects of glucocorticoids, they should be reserved for severe cases of CIDP refractory to other measures. Another autoimmune peripheral neuropathy seen in patients with AIDS is mononeuritis multiplex (Chaps.


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InternalMed_Harrison. glucocorticoids, they should be reserved for severe cases of CIDP refractory to other measures. Another autoimmune peripheral neuropathy seen in patients with AIDS is mononeuritis multiplex (Chaps. 460 and 385) due to a necrotizing arteritis of peripheral nerves. The most common peripheral neuropathy in patients with HIV infection is a distal sensory polyneuropathy (DSPN) also referred to as painful sensory neuropathy (HIV-SN), predominantly sensory neuropathy, or distal symmetric peripheral neuropathy. This condition may be a direct consequence of HIV infection or a side effect of dideoxynucleoside therapy. It is more common in taller individuals, older individuals, and those with lower CD4 counts. Two-thirds of patients with AIDS may be shown by electrophysiologic studies to have some evidence of peripheral nerve disease. Presenting symptoms are usually painful burning sensations in the feet and lower extremities. Findings on examination include a stocking-type sensory loss to


InternalMed_Harrison

InternalMed_Harrison. evidence of peripheral nerve disease. Presenting symptoms are usually painful burning sensations in the feet and lower extremities. Findings on examination include a stocking-type sensory loss to pinprick, temperature, and touch sensation and a loss of ankle reflexes. Motor changes are mild and are usually limited to weakness of the intrinsic foot muscles. Response of this condition to antiretrovirals has been variable, perhaps because antiretrovirals are responsible for the problem in some instances. When due to dideoxynucleoside therapy, patients with lower extremity peripheral neuropathy may complain of a sensation that they are walking on ice. Other entities in the differential diagnosis of peripheral neuropathy include diabetes mellitus, vitamin B12 deficiency, and side effects from metronidazole or dapsone. For distal symmetric polyneuropathy that fails to resolve following the discontinuation of dideoxynucleosides, therapy is symptomatic; gabapentin, carbamazepine, tricyclics,


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InternalMed_Harrison. metronidazole or dapsone. For distal symmetric polyneuropathy that fails to resolve following the discontinuation of dideoxynucleosides, therapy is symptomatic; gabapentin, carbamazepine, tricyclics, or analgesics may be effective for dysesthesias. Treatment-naïve patients may respond to cART.


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InternalMed_Harrison. Myopathy may complicate the course of HIV infection; causes include HIV infection itself, zidovudine, and the generalized wasting syndrome. HIV-associated myopathy may range in severity from an asymptomatic elevation in creatine kinase levels to a subacute syndrome characterized by proximal muscle weakness and myalgias. Quite pronounced elevations in creatine kinase may occur in asymptomatic patients, particularly after exercise. The clinical significance of this 1267 as an isolated laboratory finding is unclear. A variety of both inflammatory and noninflammatory pathologic processes have been noted in patients with more severe myopathy, including myofiber necrosis with inflammatory cells, nemaline rod bodies, cytoplasmic bodies, and mitochondrial abnormalities. Profound muscle wasting, often with muscle pain, may be seen after prolonged zidovudine therapy. This toxic side effect of the drug is dose-dependent and is related to its ability to interfere with the function of


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InternalMed_Harrison. wasting, often with muscle pain, may be seen after prolonged zidovudine therapy. This toxic side effect of the drug is dose-dependent and is related to its ability to interfere with the function of mitochondrial polymerases. It is reversible following discontinuation of the drug. Red ragged fibers are a histologic hallmark of zidovudine-induced myopathy.


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InternalMed_Harrison. Ophthalmologic Diseases Ophthalmologic problems occur in ~50% of patients with advanced HIV infection. The most common abnormal findings on funduscopic examination are cotton-wool spots. These are hard white spots that appear on the surface of the retina and often have an irregular edge. They represent areas of retinal ischemia secondary to microvascular disease. At times they are associated with small areas of hemorrhage and thus can be difficult to distinguish from CMV retinitis. In contrast to CMV retinitis, however, these lesions are not associated with visual loss and tend to remain stable or improve over time.


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InternalMed_Harrison. One of the most devastating consequences of HIV infection is CMV retinitis. Patients at high risk of CMV retinitis (CD4+ T cell count <100/μL) should undergo an ophthalmologic examination every 3–6 months. The majority of cases of CMV retinitis occur in patients with a CD4+ T cell count <50/μL. Prior to the availability of cART, this CMV reactivation syndrome was seen in 25–30% of patients with


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InternalMed_Harrison. AIDS. In the cART era this has dropped to close to 2%. CMV retinitis usually presents as a painless, progressive loss of vision. Patients may also complain of blurred vision, “floaters,” and scintillations. The disease is usually bilateral, although typically it affects one eye more than the other. The diagnosis is made on clinical grounds by an experienced ophthalmologist. The characteristic retinal appearance is that of perivascular hemorrhage and exudate. In situations where the diagnosis is in doubt due to an atypical presentation or an unexpected lack of response to therapy, vitreous or aqueous humor sampling with molecular diagnostic techniques may be of value. CMV infection of the retina results in a necrotic inflammatory process, and the visual loss that develops is irreversible. CMV retinitis may be complicated by rhegmatogenous retinal detachment as a consequence of retinal atrophy in areas of prior inflammation. Therapy for CMV retinitis consists of oral valganciclovir, IV


InternalMed_Harrison

InternalMed_Harrison. CMV retinitis may be complicated by rhegmatogenous retinal detachment as a consequence of retinal atrophy in areas of prior inflammation. Therapy for CMV retinitis consists of oral valganciclovir, IV ganciclovir, or IV foscarnet, with cidofovir as an alternative. Combination therapy with ganciclovir and foscarnet has been shown to be slightly more effective than either ganciclovir or foscarnet alone in the patient with relapsed CMV retinitis. A 3-week induction course is followed by maintenance therapy with oral valganciclovir. If CMV disease is limited to the eye, intravitreal injections of ganciclovir or foscarnet may be considered. Intravitreal injections of cidofovir are generally avoided due to the increased risk of uveitis and hypotony. Maintenance therapy is continued until the CD4+ T cell count remains >100 μL for >6 months. The majority of patients with HIV infection and CMV disease develop some degree of uveitis with the initiation of cART. The etiology of this is unknown;


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InternalMed_Harrison. T cell count remains >100 μL for >6 months. The majority of patients with HIV infection and CMV disease develop some degree of uveitis with the initiation of cART. The etiology of this is unknown; however, it has been suggested that this may be due to the generation of an enhanced immune response to CMV as an IRIS (see above). In some instances this has required the use of topical glucocorticoids.


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InternalMed_Harrison. Both HSV and varicella zoster virus can cause a rapidly progressing, bilateral necrotizing retinitis referred to as the acute retinal necrosis syndrome, or progressive outer retinal necrosis (PORN). This syndrome, in contrast to CMV retinitis, is associated with pain, keratitis, and iritis. It is often associated with orolabial HSV or trigeminal zoster. Ophthalmologic examination reveals widespread pale gray peripheral lesions. This condition is often complicated by retinal detachment. It is important to recognize and treat this condition with IV acyclovir as quickly as possible to minimize the loss of vision. Several other secondary infections may cause ocular problems in HIV-infected patients. P. jiroveci can cause a lesion of the choroid that may be detected as an incidental finding on ophthalmologic examination. These lesions are typically bilateral, are from half to twice the disc


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InternalMed_Harrison. Human Immunodeficiency Virus Disease: AIDS and Related Disorders 1268 diameter in size, and appear as slightly elevated yellow-white plaques. They are usually asymptomatic and may be confused with cotton-wool spots. Chorioretinitis due to toxoplasmosis can be seen alone or, more commonly, in association with CNS toxoplasmosis. KS may involve the eyelid or conjunctiva, while lymphoma may involve the retina. Syphilis may lead to a uveitis that is highly associated with the presence of neurosyphilis.


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InternalMed_Harrison. Additional Disseminated Infections and Wasting Syndrome Infections with species of the small, gram-negative, Rickettsia-like organism Bartonella (Chap. 197) are seen with increased frequency in patients with HIV infection. While it is not considered an AIDS-defining illness by the CDC, many experts view infection with Bartonella as indicative of a severe defect in cell-mediated immunity. It is usually seen in patients with CD4+ T cell counts <100/μL and is a significant cause of unexplained fever in patients with advanced HIV infection. Among the clinical manifestations of Bartonella infection are bacillary angiomatosis, cat-scratch disease, and trench fever. Bacillary angiomatosis is usually due to infection with B. henselae and is linked to exposure to flea-infested cats. It is characterized by a vascular proliferation that leads to a variety of skin lesions that have been confused with the skin lesions of KS. In contrast to the lesions of KS, the lesions of bacillary angiomatosis


InternalMed_Harrison

InternalMed_Harrison. by a vascular proliferation that leads to a variety of skin lesions that have been confused with the skin lesions of KS. In contrast to the lesions of KS, the lesions of bacillary angiomatosis generally blanch, are painful, and typically occur in the setting of systemic symptoms. Infection can extend to the lymph nodes, liver (peliosis hepatis), spleen, bone, heart, CNS, respiratory tract, and GI tract. Cat-scratch disease also is due to B. henselae and generally begins with a papule at the site of inoculation. This is followed several weeks later by the development of regional adenopathy and malaise. Infection with B. quintana is transmitted by lice and has been associated with case reports of trench fever, endocarditis, adenopathy, and bacillary angiomatosis. The organism is quite difficult to culture, and diagnosis often relies on identifying the organism in biopsy specimens using the Warthin-Starry or similar stains. Treatment is with either doxycycline or erythromycin for at


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InternalMed_Harrison. to culture, and diagnosis often relies on identifying the organism in biopsy specimens using the Warthin-Starry or similar stains. Treatment is with either doxycycline or erythromycin for at least 3 months.


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InternalMed_Harrison. Histoplasmosis is an opportunistic infection that is seen most frequently in patients in the Mississippi and Ohio River valleys, Puerto Rico, the Dominican Republic, and South America. These are all areas in which infection with H. capsulatum is endemic (Chap. 236). Because of this limited geographic distribution, the percentage of AIDS cases in the United States with histoplasmosis is only ~0.5. Histoplasmosis is generally a late manifestation of HIV infection; however, it may be the initial AIDS-defining condition. In one study, the median CD4+ T cell count for patients with histoplasmosis and AIDS was 33/μL. While disease due to H. capsulatum may present as a primary infection of the lung, disseminated disease, presumably due to reactivation, is the most common presentation in HIV-infected patients. Patients usually present with a 4to 8-week history of fever and weight loss. Hepatosplenomegaly and lymphadenopathy are each seen in about 25% of patients. CNS disease, either


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InternalMed_Harrison. HIV-infected patients. Patients usually present with a 4to 8-week history of fever and weight loss. Hepatosplenomegaly and lymphadenopathy are each seen in about 25% of patients. CNS disease, either meningitis or a mass lesion, is seen in 15% of patients. Bone marrow involvement is common, with thrombocytopenia, neutropenia, and anemia occurring in 33% of patients. Approximately 7% of patients have mucocutaneous lesions consisting of a maculopapular rash and skin or oral ulcers. Respiratory symptoms are usually mild, with chest x-ray showing a diffuse infiltrate or diffuse small nodules in ~50% of cases. The gastrointestinal tract may be involved. Diagnosis is made by silver staining of tissue, by culturing the organisms from blood, bone marrow, or tissue, or by detecting antigen in blood or urine. Treatment is typically with liposomal amphotericin B followed by maintenance therapy with oral itraconazole until the serum histoplasma antigen is <2 units, the patient has been on


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InternalMed_Harrison. in blood or urine. Treatment is typically with liposomal amphotericin B followed by maintenance therapy with oral itraconazole until the serum histoplasma antigen is <2 units, the patient has been on antiretrovirals for at least 6 months, and the CD4 count is >150 cells/μL. In the setting of mild infection, it may be appropriate to initiate therapy with itraconazole alone.


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InternalMed_Harrison. Following the spread of HIV infection to southeast Asia, disseminated infection with the fungus Penicillium marneffei was recognized as a complication of HIV infection and is considered an AIDS-defining condition in those parts of the world where it occurs. P. marneffei is the third most common AIDS-defining illness in Thailand, following TB and cryptococcosis. It is more frequently diagnosed in the rainy than the dry season. Clinical features include fever, generalized lymphadenopathy, hepatosplenomegaly, anemia, thrombocytopenia, and papular skin lesions with central umbilication. Treatment is with amphotericin B followed by itraconazole until the CD4+ T cell count is >100 cells/μL for at least 6 months.


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InternalMed_Harrison. Visceral leishmaniasis (Chap. 251) is recognized with increasing frequency in patients with HIV infection who live in or travel to areas endemic for this protozoal infection transmitted by sandflies. The clinical presentation is one of hepatosplenomegaly, fever, and hematologic abnormalities. Lymphadenopathy and other constitutional symptoms may be present. A chronic, relapsing course is seen in two-thirds of co-infected patients. Organisms can be isolated from cultures of bone marrow aspirates. Histologic stains may be negative, and antibody titers are of little help. Patients with HIV infection usually respond well initially to standard therapy with amphotericin B or pentavalent antimony compounds. Eradication of the organism is difficult, however, and relapses are common.


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InternalMed_Harrison. Patients with HIV infection are at a slightly increased risk of clinical malaria. This is particularly true for patients from nonendemic areas with presumed primary infection and in patients with lower CD4+ T cell counts. HIV-positive individuals with CD4+ T cell counts <300 cells/μL have a poorer response to malaria treatment than others. Co-infection with malaria is associated with a modest increase in HIV viral load. The risk of malaria may be decreased with TMP/SMX prophylaxis.


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InternalMed_Harrison. Generalized wasting is an AIDS-defining condition; it is defined as involuntary weight loss of >10% associated with intermittent or constant fever and chronic diarrhea or fatigue lasting >30 days in the absence of a defined cause other than HIV infection. Prior to the widespread use of cART it was the initial AIDS-defining condition in ~10% of patients with AIDS in the United States and is an indication for initiation of cART. Generalized wasting is rarely seen today with the earlier initiation of antiretrovirals. A constant feature of this syndrome is severe muscle wasting with scattered myofiber degeneration and occasional evidence of myositis. Glucocorticoids may be of some benefit; however, this approach must be carefully weighed against the risk of compounding the immunodeficiency of HIV infection. Androgenic steroids, growth hormone, and total parenteral nutrition have been used as therapeutic interventions with variable success.


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InternalMed_Harrison. Neoplastic Diseases The neoplastic diseases considered to be AIDS-defining conditions are Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and invasive cervical carcinoma. In addition, there is also an increase in the incidence of a variety of non-AIDS-defining malignancies including Hodgkin’s disease; multiple myeloma; leukemia; melanoma; and cervical, brain, testicular, oral, lung, gastric, liver, renal, and anal cancers. Since the introduction of potent cART, there has been a marked reduction in the incidence of KS (Fig. 226-33) and CNS lymphoma, such that the non-AIDS-defining malignancies now account for more morbidity and mortality in patients with HIV infection than the AIDS-defining malignancies. Rates of non-Hodgkin’s lymphoma have declined as well; however, this decline has not been as dramatic as the decline in rates of KS. In contrast, cART has had little effect on human papillomavirus (HPV)-associated malignancies. As patients with HIV infection live longer, a wider array of


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InternalMed_Harrison. as dramatic as the decline in rates of KS. In contrast, cART has had little effect on human papillomavirus (HPV)-associated malignancies. As patients with HIV infection live longer, a wider array of cancers is seen in this population. While some may only reflect known risk factors (e.g., smoking, alcohol consumption, co-infection with other viruses such as hepatitis B) that are increased in patients with HIV infection, some may be a direct consequence of HIV and are clearly increased in patients with lower CD4+ T cell counts.


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InternalMed_Harrison. Kaposi’s sarcoma is a multicentric neoplasm consisting of multiple vascular nodules appearing in the skin, mucous membranes, and viscera. The course ranges from indolent, with only minor skin or lymph node involvement, to fulminant, with extensive cutaneous and visceral involvement. In the initial period of the AIDS epidemic, KS was a prominent clinical feature of the first cases of AIDS, occurring in 79% of the patients diagnosed in 1981. By 1989 it was seen in only 25% of cases, by 1992 the number had decreased to 9%, and by 1997 the number was <1%. HHV-8 (KSHV) has been strongly implicated as a viral cofactor in the pathogenesis of KS. Clinically, KS has varied presentations and may be seen at any stage of HIV infection, even in the presence of a normal CD4+ T cell FIGuRE 226-41 Kaposi’s sarcoma in three patients with AIDS demonstrating (A) periorbital edema and bruising; (B) classic truncal distribu-tion of lesions; and (C) upper extremity lesions.


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InternalMed_Harrison. count. The initial lesion may be a small, raised reddish-purple nodule on the skin (Fig. 226-41), a discoloration on the oral mucosa (Fig. 226-34D), or a swollen lymph node. Lesions often appear in sun-exposed areas, particularly the tip of the nose, and have a propensity to occur in areas of trauma (Koebner phenomenon). Because of the vascular nature of the tumors and the presence of extravasated red blood cells in the lesions, their colors range from reddish to purple to brown and often take the appearance of a bruise, with yellowish discoloration and tattooing. Lesions range in size from a few millimeters to several centimeters in diameter and may be either discrete or confluent. KS lesions most commonly appear as raised macules; however, they can also be papular, particularly in patients with higher CD4+ T cell counts. Confluent lesions may give rise to surrounding lymphedema and may be disfiguring when they involve the face and disabling when they involve the lower extremities or


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InternalMed_Harrison. with higher CD4+ T cell counts. Confluent lesions may give rise to surrounding lymphedema and may be disfiguring when they involve the face and disabling when they involve the lower extremities or the surfaces of joints. Apart from skin, the lymph nodes, GI tract, and lung are the organ systems most commonly affected by KS. Lesions have been reported in virtually every organ, including the heart and the CNS. In contrast to most malignancies, in which lymph node involvement implies metastatic spread and a poor prognosis, lymph node involvement may be seen very early in KS and is of no special clinical significance. In fact, some patients may present with disease limited to the lymph nodes. These are generally patients with relatively intact immune function and thus the patients with the best prognosis. Pulmonary involvement with KS generally presents with shortness of breath. Some 80% of patients with pulmonary KS also have cutaneous lesions. The chest x-ray characteristically shows


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InternalMed_Harrison. best prognosis. Pulmonary involvement with KS generally presents with shortness of breath. Some 80% of patients with pulmonary KS also have cutaneous lesions. The chest x-ray characteristically shows bilateral lower lobe infiltrates that obscure the margins of the mediastinum and diaphragm (Fig. 226-42). Pleural effusions are seen in 70% of cases of pulmonary KS, a fact that is often helpful in the differential diagnosis. GI involvement is seen in 50% of patients with KS and usually takes one of two forms: (1) mucosal involvement, which may lead to bleeding that can be severe; these patients sometimes also develop symptoms of GI obstruction if lesions become large; and (2) biliary tract involvement. KS lesions may infiltrate the gallbladder and biliary tree, leading to a clinical picture of obstructive jaundice similar to that seen with sclerosing cholangitis. Several staging systems have been proposed for KS. One in common use was developed by the National Institute of Allergy and


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InternalMed_Harrison. of obstructive jaundice similar to that seen with sclerosing cholangitis. Several staging systems have been proposed for KS. One in common use was developed by the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group; it distinguishes patients on the basis of tumor extent, immunologic function, and presence or absence of systemic disease (Table 226-17).


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InternalMed_Harrison. FIGuRE 226-42 Chest x-ray of a patient with AIDS and pulmonary Kaposi’s sarcoma. The characteristic findings include dense bilateral lower lobe infiltrates obscuring the heart borders and pleural effusions. A diagnosis of KS is based on biopsy of a suspicious lesion. Histologically one sees a proliferation of spindle cells and endothelial cells, extravasation of red blood cells, hemosiderin-laden macrophages, and, in early cases, an inflammatory cell infiltrate. Included in the differential diagnosis are lymphoma (particularly for oral lesions), bacillary angiomatosis, and cutaneous mycobacterial infections.


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InternalMed_Harrison. Management of KS (Table 226-18) should be carried out in consultation with an expert since definitive treatment guidelines do not exist. In the majority of cases, effective cART will go a long way in achieving control. Antiretroviral therapy has been associated with the spontaneous regression of KS lesions. Paradoxically, it has also been associated with the initial appearance of KS as a form of IRIS. For patients in whom tumor persists or is compromising vital functions or in whom control of HIV replication is not possible, a variety of options exist. In some cases, lesions remain quite indolent, and many of these patients can be managed with no specific treatment. Fewer than 10% of AIDS patients with KS die as a consequence of their malignancy, Good Risk (Stage 0): Poor Risk (Stage 1): Parameter All of the Following Any of the Following


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InternalMed_Harrison. Good Risk (Stage 0): Poor Risk (Stage 1): Parameter All of the Following Any of the Following Human Immunodeficiency Virus Disease: AIDS and Related Disorders aDefined as unexplained fever, night sweats, >10% involuntary weight loss, or diarrhea persisting for more than 2 weeks. Observation and optimization of antiretroviral therapy Single or limited number of lesions


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InternalMed_Harrison. Combination chemotherapy with low-dose doxorubicin, bleomycin, and vinblastine (ABV) and death from secondary infections is considerably more common. Thus, whenever possible one should avoid treatment regimens that may further suppress the immune system and increase susceptibility to opportunistic infections. Treatment is indicated under two main circumstances. The first is when a single lesion or a limited number of lesions are causing significant discomfort or cosmetic problems, such as with prominent facial lesions, lesions overlying a joint, or lesions in the oropharynx that interfere with swallowing or breathing. Under these circumstances, treatment with localized radiation, intralesional vinblastine, topical 9-cis-retinoic acid, or cryotherapy may be helpful. It should be noted that patients with HIV infection are particularly sensitive to the side effects of radiation therapy. This is especially true with respect to the development of radiation-induced mucositis; doses of


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InternalMed_Harrison. that patients with HIV infection are particularly sensitive to the side effects of radiation therapy. This is especially true with respect to the development of radiation-induced mucositis; doses of radiation directed at mucosal surfaces, particularly in the head and neck region, should be adjusted accordingly. The use of systemic therapy, either IFN-α or chemotherapy, should be considered in patients with a large number of lesions or in patients with visceral involvement. The single most important determinant of response appears to be the CD4+ T cell count. This relationship between response rate and baseline CD4+ T cell count is particularly true for IFN-α. The response rate to IFN-α for patients with CD4+ T cell counts >600/μL is ~80%, while the response rate for patients with counts <150/μL is <10%. In contrast to the other systemic therapies, IFN-α provides an added advantage of having antiretroviral activity; thus, it may be the appropriate first choice for single-agent systemic


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InternalMed_Harrison. is <10%. In contrast to the other systemic therapies, IFN-α provides an added advantage of having antiretroviral activity; thus, it may be the appropriate first choice for single-agent systemic therapy for early patients with disseminated disease. A variety of chemotherapeutic agents also have been shown to have activity against KS. Four of them—liposomal daunorubicin, liposomal doxorubicin, vinblastine, and paclitaxel—have been approved by the FDA for this indication. Liposomal daunorubicin is approved as first-line therapy for patients with advanced KS. It has fewer side effects than conventional chemotherapy. In contrast, liposomal doxorubicin and paclitaxel are approved only for KS patients who have failed standard chemotherapy. Response rates vary from 23 to 88%, appear to be comparable to what had been achieved earlier with combination chemotherapy regimens, and are greatly influenced by CD4+ T cell count.


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InternalMed_Harrison. Lymphomas occur with an increased frequency in patients with congenital or acquired T cell immunodeficiencies (Chap. 374). AIDS is no exception; at least 6% of all patients with AIDS develop lymphoma at some time during the course of their illness. This is a 120-fold increase in incidence compared with the general population. In contrast to the situation with KS, primary CNS lymphoma, and most opportunistic infections, the incidence of AIDS-associated systemic lymphomas has not experienced a dramatic decrease as a consequence of the widespread use of effective cART. Lymphoma occurs in all risk groups, with the highest incidence in patients with hemophilia and the lowest incidence in patients from the Caribbean or Africa with heterosexually acquired infection. Lymphoma is a late manifestation of HIV infection, generally occurring in patients with CD4+ T cell counts <200/μL. As HIV disease progresses, the risk of lymphoma increases. The attack rate for lymphoma increases exponentially


InternalMed_Harrison

InternalMed_Harrison. of HIV infection, generally occurring in patients with CD4+ T cell counts <200/μL. As HIV disease progresses, the risk of lymphoma increases. The attack rate for lymphoma increases exponentially with increasing duration of HIV infection and decreasing level of immunologic function. At 3 years following a diagnosis of HIV infection, the risk of lymphoma is 0.8% per year; by 8 years after infection, it is 2.6% per year. As individuals with HIV infection live longer as a consequence of improved cART and better treatment and prophylaxis of opportunistic infections, it is anticipated that the incidence of lymphomas may increase.