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Chapter
9
Management Of Opportunistic Diseases
Constance A. Benson, MD
Overview
TOP
What are
the major opportunistic diseases (ODs) in patients with HIV/AIDS?
The diseases
that occur as a result of HIV-related immunodeficiency include both
opportunistic infections (OIs) and malignancies. The risk of developing
an OI has declined dramatically with the widespread use of potent
combination antiretroviral therapy (ART) (see Figure 9-1). The major
OIs that occur in patients with HIV are Pneumocystis carinii pneumonia
(the organism that causes human disease in PCP is now classified
as Pneumocystis jiroveci, but PCP remains the conventional abbreviation
in clinical use), tuberculosis, disseminated Mycobacterium avium
complex (MAC) disease, cytomegalovirus (CMV) disease, Candida esophagitis,
central nervous system (CNS) infections such as cryptococcal meningitis
or Toxoplasma encephalitis, and cryptosporidiosis. While Mycobacterium
tuberculosis is an infection that occurs in both immunocompetent
and immunosuppressed patients, it remains one of the most common
opportunistic co-infections in persons with HIV disease and is responsible
for considerable morbidity and mortality worldwide. A host of other
OIs may be seen less commonly or in patients in geographic areas
where specific infections are endemic, eg, histoplasmosis in the
central Midwest part of the U.S. or isosporiasis in South Florida
and Puerto Rico.
Figure
9-1. Decline in the Incidence of Opportunistic Infections in HIV-1-Infected
Individuals Receiving Potent Combination Antiretroviral Therapy
Source: Adapted from Palella FJ Jr, Delaney KM,
Moorman AC, et al. Declining morbidity and mortality among patients
with advanced human immunodeficiency virus infection. HIV Outpatient
Study Investigators. N Engl J Med. 1998;338:853-860. Copyright 1998
by the Massachusetts Medical Society. Modified with permission (data
extrapolated through 2000).
What factors
are associated with higher risk of developing an OI?
OIs occur primarily
in HIV-infected individuals who are not receiving either OI prophylaxis
or ART (or who have not responded to it with an increase in their
CD4 cell counts above the threshold that predicts risk of developing
an OI). The principal risk of developing a specific OI is determined
by the degree of immunosuppression, as measured by the CD4 cell
count. The CD4 threshold of risk differs for each specific OI (see
Table 9-1). It is uncommon for an OI to occur in HIV-infected individuals
with CD4 cell counts above its threshold. For patients with the
same CD4 cell count, those with high viral loads (plasma HIV RNA
levels >100,000 copies/mL) have a greater risk for developing
an OD than those with a low viral load. Other factors that contribute
to increased risk for ODs include previous exposure to or infection
with a specific pathogen, prior occurrence
of an OD, environmental exposure in the absence of a host response,
and the use of ART.
What malignancies
are associated with HIV infection?
The most common
are Kaposi sarcoma (KS) and lymphomas. There is also a modest increase
in the frequency of cervical cancer. In general, these 3 forms of
malignancies correlate with immunosuppression, meaning the frequency
increases with low CD4 cell counts, but the association is less
strong than it is with the traditional AIDS-defining ODs. The rate
of KS is approximately 20,000-fold higher with HIV infection compared
with the general population, the frequency of non-Hodgkin lymphoma
is 200- to 600-fold more frequent with HIV infection, and the rate
of cervical cancer is 5-fold greater. Both lymphomas and KS are
less frequent in the era of ART.
Pneumocystis
Jiroveci (Carinii) Pneumonia (PCP)
TOP
What are
the clinical manifestations of PCP in patients with HIV infection?
PCP usually
presents as an acute or subacute respiratory illness associated
with fever, dyspnea, nonproductive cough, and fatigue. Physical
findings on examination include tachypnea, fever, and inspiratory
rales. Rarely, disseminated Pneumocystis occurs in HIV-infected
patients with profound immunosuppression. Laboratory abnormalities
associated with PCP include leukocytosis, hypoxemia, an elevated
lactate dehydrogenase (LDH), and chest radiographic findings of
localized or diffuse interstitial infiltrates. Occasionally, nodular
or cavitary lesions may be observed. Pneumothorax in patients with
advanced HIV is almost always associated with underlying Pneumocystis
infection. The degree of hypoxemia is a measure of disease severity;
severe PCP is defined as an arterial blood gas PO2 of <70 mm
Hg with an arterial-alveolar O2 gradient (AaO2) of >35 mm Hg.
The diagnosis is confirmed by demonstrating the presence of P. jiroveci
organisms in sputum or tissue samples obtained by sputum induction,
bronchoscopy with bronchoalveolar lavage, or tissue biopsy. In the
rare circumstance in which acute PCP presents very early with a
normal chest radiograph, a gallium scan may demonstrate diffuse
uptake in the lung compatible with an interstitial inflammatory
process; however, this diagnostic test is nonspecific.
How should
you manage PCP?
The preferred
initial treatment for PCP in HIV-infected individuals is trimethoprim-sulfamethoxazole
(TMP-SMX). Route of administration (oral or parenteral) is generally
based on the severity of the disease. For those with severe PCP,
parenteral therapy with trimethoprim 15-20 mg/kg and sulfamethoxazole
75-100 mg/kg, in 6-8 hour divided doses, is recommended. In addition,
adjunctive treatment with corticosteroids, in a dose equivalent
to 40 mg twice a day of prednisone for the first 5 days, followed
by a tapering schedule of 40 mg/day for days 6-10, and then 20 mg/day
to complete 21 days of therapy, should be initiated as soon as possible
after starting treatment but preferably within the first 72 hours.
For patients with mild to moderate PCP (PO2 >70 mmHg and AaO2
gradient <35 mmHg), oral treatment with 2 double-strength tablets
of TMP-SMX every 8 hours is recommended. Gradual dose escalation
may reduce the rate of occurrence of adverse reactions to TMP-SMX.
For those unable to tolerate TMP-SMX, a number of alternative regimens
are available for treatment (see Table 9-2).
Table
9-2. Alternative Regimens for the Treatment of
Pneumocystis carinii Pneumonia in Those Unable
to Tolerate Trimethoprim and Sulfamethoxazole
Severe
(PO2 <70 mm Hg; A-a O2 gradient >35 mm Hg) |
- Pentamidine
3-4 mg/kg/d IV
- IV
Trimetrexate 45 mg/M2/d IV + Leucovorin 0.5 mg/kg IV q6h
- Primaquine
15-30 mg/d (base) po + Clindamycin 600-900 mg IV q8h
|
Mild-moderate |
- Trimethoprim
15-20 mg/kg/d po + Dapsone 100 mg/d po q8h
- Primaquine
15-30 mg/d (base) p.o. + Clindamycin 300-450 mg
po q6-8 hours
- Atovaquone
suspension 750 mg
po bid
|
What
adverse reactions occur with treatment for PCP?
Patients
should be carefully monitored for adverse reactions to treatment
and response to therapy. Many patients will demonstrate acute
worsening of signs and symptoms and have radiographic abnormalities
in the first 3-5 days of treatment. This is the rationale for
adjunctive corticosteroids in those with severe PCP. Five to 7
days of treatment may be required before a clinical response is
observed, defined as a reduction in fever, and improvement in
hypoxemia, respiratory symptoms, and radiographic abnormalities.
Adverse
reactions to treatment are common in patients with AIDS. Many
patients can be treated through these with supportive care and
adjunctive medications to ameliorate symptoms; however, severe
adverse reactions may require substituting alternative treatment
regimens. Adverse effects most often associated with TMP-SMX include
skin rash (rarely, Stevens-Johnson syndrome or toxic epidermal
necrolysis), fever, hepatotoxicity, leukopenia, thrombocytopenia,
renal dysfunction, and hyperkalemia. Major side effects of pentamidine
include pancreatitis, renal dysfunction, dysglycemia, electrolyte
abnormalities, and cardiac dysrhythmias. Toxicities commonly observed
with trimetrexate include bone marrow suppression (particularly
in those who are not treated with leukovorin), fever, rash, and
hepatitis. Dapsone may cause fever, skin rash, and methemoglobinemia
with hemolysis (particularly in those with G-6-PD deficiency).
Primaquine also causes methemoglobinemia and anemia, and clindamycin
toxicities include nausea, rash, hepatitis, Clostridium difficile
toxin-associated diarrhea, and rarely toxic megacolon. Atovaquone
is associated with nausea, vomiting, diarrhea, rash, fever, and
hepatitis.
Is
secondary prophylaxis or maintenance therapy required after treatment
of the acute episode of PCP?
All
patients with a CD4 count of <200 cells/mm3 should receive
primary prophylaxis to prevent PCP. All patients who have experienced
an episode of PCP should receive secondary prophylaxis to prevent
a recurrence of PCP. Prophylaxis should be continued for life
unless immune recovery occurs with ART. Prophylaxis for PCP should
be discontinued if the CD4 count increases to levels of >200
cells/mm3 and is sustained for at least 3 months. Prophylaxis
should be restarted if the CD4 count declines to <200 cells/mm3
or if PCP recurs regardless of CD4 cell count. Table 9-3 summarizes
recommended and alternative regimens for primary and secondary
prevention of PCP. It should be noted that TMP-SMX and dapsone
plus pyrimethamine are also adequate for prevention of toxoplasmosis
in susceptible individuals; dapsone alone, atovaquone alone, and
aerosolized pentamidine are not.
Table
9-3. Recommended and Alternative Regimens for the Prevention of
Pneumocystis carinii Pneumonia in Persons with HIV-1 Infection
Preferred |
Trimethoprim-sulfamethoxazole |
- One
double-strength tablet po qd
- One
single-strength tablet po qd
|
Alternative |
Trimethoprim-sulfamethoxazole
|
One
double-strength tablet po 3x/week
|
Dapsone |
100
mg po qd or 3x/week |
Atovaquone |
1500 mg po qd |
Dapsone
+ pyrimethamine + leucovorin |
200
mg + 75 mg + 25 mg po once/week |
Aerosolized
pentamidine (Respirgard II)
|
300
mg once/month |
Mycobacterium
Avium Comples (MAC)
TOP
What are
the symptoms of MAC?
Disseminated
M. avium complex disease is a multiorgan infection, usually occurring
in patients with AIDS who have CD4 counts of <50 cells/mm3 and
principally affecting blood and lymphoreticular organs (lymph nodes,
spleen, liver, bone marrow). Symptoms are nonspecific, usually consisting
of high fevers, night sweats, weight loss, anorexia, and fatigue.
Hepatosplenomegaly and less commonly central or peripheral lymphadenopathy
are seen. Respiratory tract disease with interstitial or occasionally
lobar or cavitary pulmonary infiltrates is a less common manifestation
but may be seen in the context of multiorgan infection. Although
there are no specific laboratory abnormalities associated with disseminated
MAC, isolated elevation of alkaline phosphatase, marked anemia,
and leukopenia or thrombocytopenia secondary to bone marrow infiltration
may occur. The diagnosis is confirmed by the isolation of the organism
from a biopsy or a sample obtained for culture from blood or involved
tissue; 80%-85% of those with disseminated multiorgan disease have
a positive mycobacterial blood culture. Blood cultures may require
7-10 days of incubation before growth of M. avium is detectable.
What is
the recommended approach to treatment for disseminated MAC?
Disseminated
MAC should be treated with a combination of clarithromycin 500 mg
twice a day or azithromycin 500-600 mg/day plus ethambutol 15 mg/kg/day.
The addition of rifabutin, 300-450 mg/day, as a third drug decreases
the occurrence of relapse due to drug-resistant mycobacteria and
is associated with improved survival in profoundly immunosuppressed
individuals. This approach should be considered for those with very
low CD4 cell counts who are not receiving or responding to ART.
Treatment should be continued for life unless immune recovery occurs
following ART that results in an increase in CD4 cells to levels
>100/mm3 sustained for at least 6 months. In this setting, antimycobacterial
therapy for those who have completed at least 12 months of effective
treatment and have no signs or symptoms of disease may be discontinued.
Therapy should be re-started if the CD4 cell count again declines
to <100/mm3.
Primary prophylaxis
to prevent disseminated M. avium complex disease is recommended
for all HIV-infected adults and adolescents who have a CD4 count
of <50 cells/mm3. The preferred regimens are azithromycin 1200
mg once a week or clarithromycin 500 mg twice a day. Azithromycin
is preferred when patients are receiving other drugs metabolized
by the cytochrome P450 3A4 isoenzyme system, to avoid drug-drug
interactions with clarithromycin. Rifabutin 300 mg/day is a second
line alternative for prophylaxis, but is less effective than azithromycin
or clarithromycin, and also must be monitored and dose-adjusted
when used with other drugs metabolized by the cytochrome 3A4 isoenzyme.
Cytomegalovirus
Infection (CMV)
TOP
What are
the major clinical syndromes associated with CMV infection in patients
with HIV infection and how are they diagnosed?
Cytomegalovirus
retinitis is the most common CMV-associated clinical syndrome observed
in patients with AIDS. Patients with CMV retinitis involving peripheral
portions of the retina may have no symptoms, or only minor visual
complaints such as floaters or peripheral visual field defects.
Central lesions may result in central scotomata and loss of central
vision. The diagnosis is based on ophthalmologic examination demonstrating
creamy white retinal exudates with hemorrhage; lesions obscure visualization
of underlying vessels and other retinal structures. Retinitis is
bilateral in up to 20% of patients. Disease progresses rapidly to
blindness unless treated.
The second-most common clinical syndrome associated with CMV disease
is gastrointestinal disease, either CMV colitis or CMV esophagitis.
CMV colitis presents with fever, diarrhea, weight loss, and colon
ulceration often with bleeding. Appropriate diagnosis usually requires
colonoscopy and biopsy of ulcerations; tissue histopathology confirms
the presence of characteristic intranuclear inclusions in mucosal
cells or CMV antigens on immunohistochemical staining. CMV esophagitis
presents with fever, odynophagia, and retrosternal pain. Exudative
ulcers are demonstrated by esophageal endoscopic exam. Biopsy and
histopathologic examination are necessary to confirm the diagnosis.
Other less common CMV clinical syndromes in patients with AIDS are
CMV encephalitis/encephalopathy, interstitial pneumonitis, hepatitis,
and pancreatitis.
What is
the recommended treatment for CMV retinitis?
CMV retinitis
should be managed in cooperation with an experienced ophthalmologist.
For patients with CMV retinitis that is immediately sight-threatening
(central lesions approaching or involving the optic nerve or the
fovea) systemic therapy with either IV ganciclovir or oral valganciclovir
is the preferred initial treatment; many experts would also recommend
surgical treatment with a ganciclovir intraocular implant (see Table
9-4). IV ganciclovir or oral valganciclovir is administered in an
acute "induction" dose for 14-21 days, followed by a once-a-day
chronic maintenance therapy dose. This approach is superior to other
alternatives for preventing or delaying disease progression and
provides systemic treatment to prevent other organ system involvement.
If effective ART is not administered or patients remain immunosuppressed,
the ocular implant should be replaced every 7-8 months. For patients
with peripheral CMV retinitis that is not immediately sight-threatening,
oral valganciclovir is the preferred treatment because of its ease
of administration compared with other parenteral alternatives.
Chronic maintenance
treatment for CMV retinitis should be continued for life unless
ART results in a sustained increase in CD4 counts to levels of >100
cells/mm3 for at least 6 months. If the CD4 count again declines
to <100 cells/mm3, maintenance therapy should be reinitiated.
Immune recovery vitritis is a recognized complication of acute rises
in CD4 cell counts and decreases in plasma HIV RNA levels following
initiation of ART. It may be associated with an acute decrease in
visual acuity due to the inflammatory cells clouding the vitreous
fluid. Treatment with local corticosteroids while continuing anti-CMV
therapy is associated with rapid improvement in most patients.
Table
9-4. Treatment Options for Cytomegalovirus Disease
Ganciclovir
implant |
N/A |
Replace
every 7-8 months |
Oral
valganciclovir |
900
mg bid x 14-21d |
900
mg/d |
IV
ganciclovir |
5
mg/kg bid x
14-21d |
5
mg/kg/d |
Foscarnet |
90
mg/kg bid x
14-21d |
90
mg/kg/d |
IV
cidofovir
(+ probenecid)
|
5 mg/kg
once/w x
2
wks
|
5
mg/kg every 2 weeks |
What is
the recommended treatment for CMV gastrointestinal disease?
Treatment with
either oral valganciclovir or IV ganciclovir or IV foscarnet is
the recommended approach to treatment of CMV esophagitis or CMV
colitis. In general, clinical symptoms and signs resolve within
2-3 weeks, and the suggested duration of treatment is 21-28 days,
depending on the severity of the clinical presentation. Chronic
maintenance treatment is not recommended unless recurrent episodes
occur.
Strategies for treatment in those with relapse or progressive disease
include either re-induction followed by maintenance therapy with
the same agent, or switching to an alternative agent, a combination
of 2 agents, or specifically for those with CMV retinitis, systemic
therapy coupled with intravitreal injection. Recurrent or progressive
disease should be managed by an expert.
Candida
Esophagitis
TOP
What are
the presenting signs and symptoms of Candida esophagitis and how
is it diagnosed?
The most common
manifestations of Candida esophagitis are fever, anorexia, odynophagia,
and retrosternal pain. Occasionally, nausea and rarely UGI bleeding
from ulceration may occur. Esophagoscopy reveals adherent whitish
plaques with shallow ulcers surrounded by erythematous borders.
Invasive esophageal candidiasis can occur in the absence of oral
candidiasis and must be distinguished from esophagitis due to CMV,
herpes simplex virus, and aphthous esophagitis, all of which may
be seen in patients with HIV infection. Isolation of Candida species
in culture from a specimen obtained from the mucosal surface or
the base of an ulcer provides supportive information but is not
diagnostic, as colonization of mucosal surfaces with Candida is
common in immunosuppressed individuals, particularly those who are
receiving antibacterial therapies such as TMP-SMX for prophylaxis
of PCP. The diagnosis can be confirmed by a biopsy of the ulcer
and demonstration of yeast forms in tissue. The finding of oral
candidiasis associated with esophageal symptoms has a positive predictive
value of close to 100% for Candida esophagitis. In patients with
oral candidiasis and esophageal symptoms empiric therapy for Candida
esophagitis should be given. If there is no clinical response after
5-7 days, upper endoscopy should be performed.
How do you
treat Candida esophagitis?
Candida esophagitis
requires systemic therapy. A number of options are available; however,
the preferred treatment is fluconazole 100 mg/d for 14 days. Ketoconazole
and itraconazole are effective alternatives, but drug-drug interactions
with other anti-HIV therapies are common, and absorption is diminished
in those with primary or drug-induced hypo- or achlorhydria. For
patients unable to tolerate oral therapy, parenteral amphotericin
B is effective. Chronic maintenance therapy or secondary prophylaxis
is not recommended, but may be considered for patients who have
frequent recurrent episodes. Chronic suppressive therapy with fluconazole
has been associated with an increased risk of fluconazole (and other
azole) resistant disease.
Central
Nervous System Diseases
TOP
How do you
distinguish cryptococcal meningitis from toxoplasmic encephalitis
and CNS lymphoma in HIV-infected patients?
Patients with
AIDS and a CD4 count of <200 cells/mm3 may be at risk for developing
CNS OIs such as cryptococcal meningitis or toxoplasmosis, as well
as CNS lymphoma; most infections occur in those with CD4 counts
of <100 cells/mm3. Toxoplasmic encephalitis is rare in patients
who are seronegative for Toxoplasma gondii (negative IgG antibody).
CNS infection due to T. gondii and Cryptococcus spp. as well as
CNS lymphoma may be relatively insidious in onset and associated
with symptoms of fever, headache, and mental status changes. Focal
neurological deficits and seizures are more likely to occur with
toxoplasmic encephalitis and CNS lymphoma, although they sometimes
occur in those with cryptococcal meningitis as well. The best diagnostic
tests for a differential diagnosis of CNS disease are radiographic
imaging of the CNS (with either a contrast-enhanced computerized
tomographic [CT] scan or magnetic resonance imaging [MRI] scan)
and lumbar puncture with cerebrospinal fluid (CSF) examination.
Multiple localized enhancing lesions are common with toxoplasmic
encephalitis; MRI is more sensitive than a CT scan for detecting
these. CNS lymphoma is more likely to be associated with single
and less commonly multiple space-occupying lesions, while cryptococcal
meningitis is only rarely associated with space-occupying lesions.
The CSF may demonstrate a normal to mild lymphocytic pleocytosis,
normal to slightly elevated protein, and normal to mildly decreased
glucose for each, but a CSF cryptococcal antigen will be positive
in 99%-100% of individuals with cryptococcal meningitis. Confirmation
of the diagnosis of toxoplasmic encephalitis generally requires
either demonstration of the organism in CSF by polymerase chain
reaction (PCR) or culture (may not be routinely available) or a
brain biopsy and demonstration of the organism in tissue. In practice,
a trial of therapy is usually the first diagnostic tool for patients
who have suggestive neuroimaging and positive Toxoplasma serology.
Brain biopsy is reserved for patients who do not respond to empiric
therapy. A brain biopsy is necessary to confirm the diagnosis of
CNS lymphoma.
How do you
treat cryptococcal meningitis?
Amphotericin
B (0.7 mg/kg/d or the dose equivalent of liposomal or lipid complex
amphotericin B), combined with flucytosine 100 mg/kg/day in divided
doses, for the first 2 weeks, is the recommended initial treatment
for cryptococcal meningitis. If a treatment response is evident
this regimen is followed by fluconazole 400 mg/day for an additional
8 weeks or until CSF cultures are negative. The CSF opening pressure
should always be measured when a lumbar puncture is performed, and
if elevated above 200 mg H2O, measures to reduce the pressure should
be implemented. These may include serial lumbar puncture with CSF
drainage sufficient to reduce the pressure by 50%, or in the case
of severe increased intracranial pressure, the use of a lumbar drain
or ventriculoperitoneal shunt. Secondary prophylaxis or chronic
maintenance therapy with fluconazole, 200 mg/day, should be continued
for life unless ART results in immune recovery. In this instance,
maintenance therapy may be discontinued for those who have successfully
completed a course of therapy for cryptococcal meningitis, have
no residual signs or symptoms, and have a sustained increase in
CD4 count to levels of >100-200 cells/mm3 for at least 6 months.
Maintenance therapy should be re-initiated if the CD4 count again
decreases to <100-200 cells/mm3.
Mycobacterium
Tuberculosis
TOP
Does the
presentation of tuberculosis differ in HIV-infected and non-HIV-infected
individuals?
Patients with
HIV infection have an increased risk of infection with Mycobacterium
tuberculosis following exposure to a person with active disease,
and an increased risk of developing active disease following an
exposure. The risk of developing active disease is 30%-40% in the
first year following a new exposure, and for HIV-infected patients
with a positive tuberculin skin test related to prior TB exposure,
the risk of developing active disease may be as high as 7%-8% per
year.
For patients with a CD4 count of >250 cells/mm3, the clinical
signs and symptoms of tuberculosis are generally the same as for
HIV-noninfected persons. Pulmonary tuberculosis accompanied by fever,
cough, sputum production, chest pain, night sweats, weight loss,
and anorexia is the principal manifestation. As immunosuppression
progresses, the likelihood of extrapulmonary or disseminated (miliary)
disease increases, although in most instances, pulmonary involvement
is also present. Chest radiograph demonstrates lobar consolidation
with cavitation, usually involving upper lobes, when reactivation
tuberculosis is present. In those with primary tuberculous pneumonia,
lower lobe infiltrates are more common. Hilar or mediastinal lymphadenopathy,
pleural effusion, and interstitial infiltrates may be more common
in patients with lower CD4 cell counts.
How do you
diagnose TB in persons with HIV?
The diagnosis
is the same as for non-HIV-infected persons, relying on a combination
of compatible clinical signs and symptoms, radiographic findings,
a positive tuberculin skin test, and a sputum sample demonstrating
acid-fast bacilli (AFB). The diagnosis is confirmed by culture of
the organism from sputum, blood, or other tissue. However, patients
with advanced immunosuppression may have less extensive consolidation
or lung cavitation, and sputum AFB smears may be positive in a lower
proportion, because of the lower mycobacterial burden in the lung.
Also, tuberculin skin tests are less likely to be positive because
of impaired cell-mediated immune function. In immunocompromised
patients, more aggressive means for making a diagnosis may be necessary,
such as bronchoscopy with bronchoalveolar lavage or transbronchial
biopsy to obtain samples for AFB smear and culture. Biopsy or culture
of specimens obtained from extrapulmonary sites such as bone marrow
and lymph nodes may be useful. All initial isolates of M. tuberculosis
should be tested for susceptibility to antimycobacterial drugs,
and susceptibility testing should guide the choice of initial treatment.
How do you
treat tuberculosis in patients with HIV infection?
The recommendations
for treatment of tuberculosis in patients with HIV infection depend
in part on whether or not patients are on ART, and if they are,
the specific antiretroviral regimens employed. All patients should
receive directly observed therapy. See Adult OI Tables 2 - 7 for
the recommendations for treatment of latent tuberculosis and drug-susceptible
tuberculosis disease. Treatment with 4 drugs (isoniazid, rifampin
or rifabutin, ethambutol, and pyrazinamide) is recommended either
for the first 2 months of therapy or until results of susceptibility
testing are available. If patients have drug-susceptible disease,
2 drugs, isoniazid and rifampin or rifabutin, should then be continued
for at least 18 additional weeks. The continuation phase of therapy
should be extended to 28 weeks (total duration of 9 months) for
HIV-infected patients with advanced immunosuppression (CD4 count
of <100 cells/mm3) or who have an inadequate initial response
or cavitary disease. Rifabutin should replace rifampin and doses
should be appropriately adjusted for those who are receiving ART
with agents likely to interact with rifamycins. The timing of initiation
of ART and the most appropriate ART regimen for use in conjunction
with antimycobacterial therapy remain controversial. Concurrent
ART and tuberculosis treatment should be managed by an expert.
Malignancies
TOP
How does
Kaposi sarcoma (KS) present?
KS is a poorly
understood multicentric tumor of endothelial cells. The cause is
human herpesvirus 8 (HHV-8), an infection that is more frequent
in men who have sex with men. The mechanism of transmission is unclear,
but the best evidence suggests transmission via saliva and semen.
Many carry the virus with no consequences; it causes disease primarily
in the presence of immunosuppression. The presentation is highly
characteristic, with multiple purple to brown-black macules, or
nodules that are usually asymptomatic and occur most frequently
on the legs, face, oral cavity, or genitalia. The major complications
include lymphedema (especially of the legs, face, and genitalia)
and visceral involvement. Visceral involvement is common in the
lung and GI tract, but is usually asymptomatic.
How do you
diagnose KS?
The skin lesions
are usually sufficiently characteristic to make this diagnosis clinically
based on appearance, but a biopsy should be done when there is a
need for confirmation. The differential diagnosis includes bacillary
angiomatosis (which can be proven by biopsy with silver stain),
hematoma, nevus, hemangioma, B-cell lymphoma, and pyogenic granuloma.
When there is visceral involvement, the usual method used to establish
the diagnosis is endoscopic examination to show typical mucosal
surface lesions. With lung involvement, the x-ray is variable and
may show nodules, infiltrates, effusions, and/or mediastinal/hilar
nodes. Lung biopsy is often negative, but the bronchoscopic exam
often shows a characteristic cherry-red bronchial nodule. With GI
tract involvement, the usual screening test is stool for occult
blood, and endoscopy is the usual method to make the diagnosis by
showing a hemorrhagic nodule; the biopsy is often negative because
of the submucosal location of the tumor.
How do you
treat KS?
Many patients
require no therapy except possibly makeup to cover the characteristic
lesions. Topical treatment for skin involvement includes vinblastine,
Panretin gel, liquid nitrogen, radiation, cryosurgery, or laser.
Systemic chemotherapy is preferred when there is an extensive burden,
defined as >25 skin lesions, symptomatic visceral involvement,
extensive edema, systemic (B) symptoms, or failure to respond to
local treatment. The favored forms of chemotherapy are liposomal
anthracyclines (Doxil or DaunoXome) or, less frequently, paclitaxel
(Taxol). Immune reconstitution with ART is associated with a substantial
reduction in the frequency of KS and a therapeutic improvement in
those who already have these lesions. It should be noted that there
is no cure for KS, and the goal of local therapy or systemic chemotherapy
is to reduce tumor burden and relieve symptoms.
What
lymphomas are associated with HIV infection?
The subtypes
of lymphomas associated with HIV infection include B-cell large
cell lymphoma, primary body effusion lymphomas, B-cell CNS lymphoma,
Burkitt lymphoma, plasmablastic lymphoma, and Hodgkin disease. The
most common is non-Hodgkin lymphoma.
What are
the symptoms of non-Hodgkin lymphoma (NHL)?
Compared with
the general population, patients with this complication have high
rates of stage IV disease with systemic (B) symptoms and sparse
node involvement. Common symptoms are fever of unknown origin, liver
dysfunction, marrow suppression, lung disease (effusions, multinodular
infiltrates, mass lesions, diffuse infiltrates, and/or hilar adenopathy),
GI involvement (any level with pain and weight loss), and CNS with
mass lesions.
How do you
diagnose lymphomas?
Fine needle
aspirates of enlarged nodes are helpful if positive, but false negatives
are common. Biopsy is usually necessary.
How are
lymphomas treated and what should be expected?
The usual treatment
is chemotherapy with cyclophosphamide, doxorubicin, adriamycin,
vincristine, and prednisone (CHOP); methotrexate, bleomycin, doxorubicin,
cyclophosphamide, vincristine, and dexamethasone + G-CSF (M-BACOD);
or etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin
(EPOCH). Response rates are 50%-60%, but the long-term prognosis
is poor unless there is immune reconstitution with ART.
How do you
diagnose and treat primary CNS lymphomas?
The typical
presentation is confusion, headache, memory loss, focal neurologic
changes, usually without fever and usually with a CD4 cell count
of <50/mm3. The MRI shows single or multiple lesions that are
isodense or hypodense. The differential diagnosis is primarily toxoplasmosis.
Factors suggesting CNS lymphoma are the characteristic MRI findings,
negative T. gondii serology, failure to respond to empiric treatment
of toxoplasmosis within 1-2 weeks, thallium single-photon emission
computed tomography (thallium SPECT) scan results, and CSF positive
by polymerase chain reaction (PCR) for Epstein Barr virus (EBV)
DNA. The definitive diagnosis can be made by stereotactic brain
biopsy. Treatment is radiation and corticosteroids, often combined
with chemotherapy. The prognosis is poor without immune reconstitution.
- The risk
of persons with HIV developing specific ODs is related to the
degree of their immunosuppression, as measured by the CD4 cell
count.
- All patients
with a CD4 count of <200 cells/mm3 should receive primary prophylaxis
to prevent PCP. PCP usually presents as an acute or subacute respiratory
illness associated with fever, dyspnea, nonproductive cough, and
fatigue.
- All patients
with a CD4 cell count of <50/mm3 should receive primary prophylaxis
to prevent disseminated MAC. Disseminated MAC is a multiorgan
infection that usually occurs at CD4 cell counts of <50/mm3.
Symptoms are nonspecific, usually consisting of high fever, night
sweats, weight loss, anorexia, and fatigue.
- CMV retinitis,
the most common CMV-associated clinical syndrome, progresses rapidly
to blindness unless treated. CMV gastrointestinal disease, either
colitis or esophagitis, presents with fever, diarrhea, weight
loss, and colon ulceration often with bleeding.
- The most
common manifestations of Candida esophagitis are fever, anorexia,
odynophagia, and retrosternal pain. Treatment requires systemic
therapy.
- Patients
with a CD4 count of <200 cells/mm3 are at risk for developing
CNS ODs such as cryptococcal meningitis or toxoplasmosis, as well
as CNS lymphoma. After initial treatment, chronic maintenance
therapy should be continued for life unless immune recovery occurs
as a result of ART.
- Patients
with HIV are at increased risk of infection with Mycobacterium
tuberculosis and of developing active tuberculosis. Immunosuppression
increases the likelihood of extrapulmonary or disseminated (miliary)
disease. Because tuberculin skin tests are less likely to be positive
in immunocompromised patients, more aggressive means for making
a diagnosis may be necessary.
All HIV-infected patients with active tuberculosis should receive
directly observed therapy. Treatment of tuberculosis in persons
with HIV co-infection should be managed by an expert because treatment
is complex and the infection is potentially life-threatening.
- The major
complications of KS, a multicentric tumor of endothelial cells,
include lymphedema (especially of the legs, face, and genitalia)
and visceral involvement. Extent of involvement determines whether
treatment is required and whether it is topical or systemic.
- The most
common lymphoma associated with HIV is non-Hodgkin lymphoma. Common
symptoms are fever of unknown origin, liver dysfunction, marrow
suppression, lung disease, GI involvement (any level with pain
and weight loss), and CNS mass lesions.
Suggested
Resources
TOP
Leav BA, Mackay
M, Ward HD. "Cryptosporidium species: New insights
and old challenges". Clin Infect Dis. 2003;36:903-908.
Official
statement of ATS, CDC and IDSA: Treatment of tuberculosis. Am
J Crit Care Med. 2003;167:603-662. Accessed 1/04.
USPHS/IDSA
Guidelines for the Prevention of Opportunistic Infections in Persons
Infected with HIV. Washington DC: U.S. Department of Health
and Human Services. Nov 28, 2001. Accessed 1/04.
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