1578 PART 5 Infectious Diseases

suggest that these factors as well as inflammatory cytokines may be

involved in the pathogenesis of this syndrome.

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 ART 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

ART has resulted in an increase in the prevalence of milder forms of

this disorder.

Seizures may be a consequence of opportunistic infections, neoplasms, or HIV encephalopathy (Table 202-16). 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,

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 more seizures, suggesting that anticonvulsant therapy

is indicated in all patients with HIV infection and seizures unless

a rapidly correctable cause is found. Due to a variety of drug–drug

interactions between antiseizure medications and antiretrovirals, drug

levels need to be monitored carefully.

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. 210), stroke, and reactivation of Chagas’ disease.

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 ART. 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 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. 202-41) 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 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 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. jirovecii prophylaxis provides adequate primary

protection against toxoplasmosis. Secondary prophylaxis/maintenance

therapy for toxoplasmosis may be discontinued in the setting of effective ART and increases in CD4+ T-cell counts to >200/μL for 6 months.

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. 133). While ~80% of

TABLE 202-16 Causes of Seizures in Patients with HIV Infection

DISEASE

OVERALL

CONTRIBUTION TO

FIRST SEIZURE, %

FRACTION OF PATIENTS

WHO HAVE SEIZURES, %

HIV encephalopathy 24–47 7–50

Cerebral toxoplasmosis 28 15–40

Cryptococcal meningitis 13 8

Primary central nervous

system lymphoma

4 15–30

Progressive multifocal

leukoencephalopathy

1 20

Source: From DM Holtzman et al: Am J Med 87:173, 1989.

FIGURE 202-41 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.

1579CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

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 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 ART, most patients with PML died within 3–6 months of the

onset of symptoms. Paradoxical worsening of PML has been seen with

initiation of ART 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 ART for their HIV disease. Despite having a significant impact

on survival, only ~50% of patients with HIV infection and PML show

neurologic improvement with ART. 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 ART.

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. Most 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 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.

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 cocaine or amphetamine use.

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

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 most cases of myelopathy seen

in patients with HIV infection. However, it should be included in the

differential diagnosis. 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 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.

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 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. 196), neurosyphilis (Chap. 177), infection with herpes

simplex (Chap. 187) or varicella-zoster (Chap. 188), TB (Chap. 173),

and lymphoma (Chap. 104).

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. 439). 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.  439 and 356) 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 ART

with dideoxynucleosides. 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

1580 PART 5 Infectious Diseases

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, or analgesics may be effective

for dysesthesias. Treatment-naïve patients may respond to ART.

Myopathy may complicate the course of HIV infection; causes

include HIV infection itself, zidovudine, and the generalized wasting

syndrome (discussed below). 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 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 mitochondrial polymerases.

It is reversible following discontinuation of the drug. Red ragged fibers

are a histologic hallmark of zidovudine-induced myopathy.

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.

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 ART,

this CMV reactivation syndrome was seen in 25–30% of patients with

AIDS. In the ART 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 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 ART. 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.

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. jirovecii 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

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.

Additional Disseminated Infections and Wasting Syndrome

Infections with species of the small, gram-negative, Rickettsia-like

organism Bartonella (Chap. 167) 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 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 is also due to infection with 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, PCR, and/

or seroconversion. Treatment is with either doxycycline or erythromycin for at least 3 months.

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. 207).

Because of this limited geographic distribution, histoplasmosis is only

seen in approximately 0.5% of AIDS cases in the United States. 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 4- to 8-week history of fever and weight

loss. Hepatosplenomegaly and lymphadenopathy are each seen in

1581CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

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 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.

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 resembling the lesions

of Molluscum contagiosum. Treatment is with amphotericin B followed

by itraconazole until the CD4+ T-cell count is >100 cells/μL for at least

6 months.

Visceral leishmaniasis (Chap. 221) 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 detected by PCR and, with

special techniques, isolated from cultures of bone marrow aspirates.

Histologic stains are often diagnostic but may be negative. 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.

Patients with HIV infection are at a slightly increased risk of infection with malaria and of clinical malaria. This is particularly true for

patients from nonendemic areas who are at risk for 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.

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 ART it was the initial AIDS-defining condition in

~10% of patients with AIDS in the United States. 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.

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 ART, there

has been a marked reduction in the incidence of KS (Fig. 202-34). The

non-AIDS-defining malignancies now account for more morbidity

and mortality in patients with HIV infection than the AIDS-defining

malignancies and are responsible for approximately 10% of the deaths

in patients with HIV infection. Rates of non-Hodgkin’s lymphoma

have declined; however, this decline has not been as dramatic as the

decline in rates of KS. In contrast, ART 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.

Kaposi’s sarcoma is a multicentric neoplasm consisting of multiple

vascular nodules appearing in the skin, mucous membranes, and

viscera. The clinical course of KS 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 count.

The initial lesion may be a small, raised, reddish-purple nodule on the

skin (Fig. 202-42), a discoloration on the oral mucosa (Fig. 202-34D),

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

A B C

FIGURE 202-42 Kaposi’s sarcoma in three patients with AIDS demonstrating (A) periorbital edema and bruising; (B) classic truncal distribution of lesions; and (C) upper

extremity lesions.

1582 PART 5 Infectious Diseases

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 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

bilateral lower lobe infiltrates that obscure the margins of the mediastinum and diaphragm (Fig. 202-43). 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 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 202-17).

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.

Management of KS (Table 202-18) should be carried out in consultation with an expert since definitive treatment guidelines do not exist.

In the majority of cases, effective ART 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, 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 easily accessible

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 radiation directed at mucosal surfaces, particularly in the head and

neck region, should be adjusted accordingly. The second indication for

KS-directed treatment is for patients with a large number of lesions

or in patients with visceral involvement. In these patients, systemic

therapy, either IFN-α or chemotherapy, should be considered. 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

FIGURE 202-43 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.

TABLE 202-17 National Institute of Allergy and Infectious Diseases

AIDS Clinical Trials Group TIS Staging System for Kaposi’s Sarcoma

PARAMETER

GOOD RISK (STAGE 0): ALL

OF THE FOLLOWING

POOR RISK (STAGE 1):

ANY OF THE FOLLOWING

Tumor (T) Confined to skin and/or lymph

nodes and/or minimal oral

disease

Tumor-associated edema

or ulceration

Extensive oral lesions

GI lesions

Nonnodal visceral lesions

Immune system (I) CD4+ T-cell count ≥200/μL CD4+ T-cell count <200/μL

Systemic illness (S) No B symptomsa B symptomsa

 present

Karnofsky performance

status ≥70

Karnofsky performance

status <70

No history of opportunistic

infection, neurologic disease,

lymphoma, or thrush

History of opportunistic

infection, neurologic

disease, lymphoma, or

thrush

a

Defined as unexplained fever, night sweats, >10% involuntary weight loss, or

diarrhea persisting for more than 2 weeks.

TABLE 202-18 Management of AIDS-Associated Kaposi’s Sarcoma

Observation and optimization of antiretroviral therapy

Single or limited number of lesions

Radiation

Intralesional vinblastine

Cryotherapy

Extensive disease

Initial therapy

 Interferon α (if CD4+ T cells >150/μL)

 Liposomal daunorubicin

Subsequent therapy

 Liposomal doxorubicin

 Paclitaxel

Combination chemotherapy with low-dose doxorubicin, bleomycin, and

vinblastine (ABV)

Targeted radiation