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Appendixes
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A
C inical Manifestations of HIV Infection
OPPORTUNISTIC INFECTIONS
The deleterious effects inflicted on the immune system following HIV
infection result in life-threatening opportunistic infections characterized
by an aggressive clinical course, resistance to therapy, and a high rate of
relapse. Opportunistic infections are the most common presenting clinical
manifestations that ultimately lead to a diagnosis of AIDS (see Appendix
E). The clinical recognition of these infections requires a high degree of
suspicion, a familiarity with the many complexities of AIDS-related
infections, and expert microbiological assistance.
Treatment of the varied AIDS-related opportunistic infections is as
complex as their diagnosis. The duration of therapy is frequently long,
and drug toxicities are seen much more often than when the same anti-
biotics are used in other patient populations.
Protozoal Infections
Pneumocystis carinii Pneumonia
Pneumocystis carinii pneumonia (PCP) is the most common AIDS-
related opportunistic infection in U.S. patients, accounting for over 50
percent of all initial AIDS diagnoses. Patients with PCP typically com-
plain of fever, cough (usually nonproductive or productive of clear to
white sputum), shortness of breath and dyspnea on exertion, and chest
281
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282 APPENDIX A
tightness. Some or all of these symptoms are seen in approximately 80
percent of patients at the time of diagnosis. The time course between
onset and medical evaluation is variable, ranging from several days in
some cases to as long as two or more months in others (Kovacs et al.,
1984).
At the time of PCP diagnosis, the chest X-ray is usually abnormal.
More than 95 percent of cases show some increase in bronchovascular/
interstitial markings. These infiltrates are typically diffuse. Pleural effu-
sions are distinctly uncommon, and if seen suggest a secondary process.
Similarly, mediastinal adenopathy is uncommonly associated with PCP
alone (Catterall et al., 19851.
Identification of the organism is required before a diagnosis of PCP can
be made. Tissue diagnosis can be made using several techniques. Initially,
transbronchial biopsies were performed in most individuals, but broncho-
alveolar ravage either with or without bronchoscopy is nearly as sensitive
and is less invasive (Broaddus et al., 1985; Ognibene et al., 19841. In
addition, induced sputum has been increasingly used to make a diagnosis.
Sputum must be examined with particular care to find PCP organisms, but
this procedure avoids more than 50 percent of invasive procedures (Bibgy
et al., 19861. Serologic testing is not sufficient for the diagnosis, and
empiric therapy should be avoided in most cases because of frequent drug
toxicity.
The treatment of PCP consists of either trimethoprim-sulfamethoxazole
or pentamidine isothianate (Hughes et al., 19781. However, toxicities are
common with these drugs (Gordin et al., 1984), therapy must be longer
than in other settings, and there is a high rate of relapse (Haverkos, 19841.
Because conventional therapy is only partially elective with PCP, and
because PCP is the most common direct cause of death in AIDS, there is
currently a great deal of interest in identifying additional effective
therapies. Trials are being conducted with dapsone (Hughes and Smith,
1984) and difluoromethoornithine (DEMO). Trials of prophylaxis using
trimethoprim-sulfamethoxazole are also being conducted (Kaplan et al.,
19861.
Toxoplasma gondii
Toxoplasmosis is one of the most common causes of central nervous
system (CNS) disease in AIDS (Luft et al., 1984; Navia et al., 1986; Wong
et al., 19844. It is also one of the most treatable AIDS-related opportu-
nistic infections. Clinical features of CNS infection with Toxoplasma
gondii include seizures, focal necrologic deficits, and encephalopathy.
Because serologic testing for Toxoplasma is insensitive and nonspecific,
diagnosis requires tissue confirmation. However, the morbidity of brain
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APPENDIX A 283
biopsy dictates that this is often not performed. Instead, many clinicians
attempt empiric therapy in patients strongly suspected of having CNS
toxoplasmosis.
A diagnosis of T. gondii infection of the CNS can be suspected when a
patient with AIDS or in an AIDS risk group complains of seizures or focal
necrologic deficits (Luft et al., 19841. Although encephalopathy can be
seen with toxoplasmosis, it is more suggestive of HIV-related encepha-
lopathy. The diagnosis of Toxoplasma CNS infection can be confirmed by
computerized tomography (CT) scanning or magnetic resonance imaging
(MRI) procedures. These typically show multiple lesions deep in the brain
tissue with ring enhancement. These lesions are nearly diagnostic for
toxoplasmosis in this population, and the only common alternative
diagnosis considered is CNS lymphoma.
Therapy for toxoplasmosis is currently limited to a combination of
pyramethamine and sulfadiazine with folinic acid. Response to therapy is
generally prompt, with improvement on radiologic imaging seen within
two weeks in most cases. However, relapses at some point after therapy
are nearly universal. Also, drug toxicity is common and includes skin
rashes, neutropenia, and thrombocytopenia. There is no standard second-
line drug for the treatment of toxoplasmosis, but clindamycin is occasion-
ally attempted.
After a two- to three-week course of sulfadiazine-pyramethamine, CT
or MRI scanning can be repeated. If substantial regression of previously
noted lesions has occurred, this is taken as presumptive evidence of the
diagnosis. If, on the other hand, the disease is stable or worse, a brain
biopsy can be performed to evaluate the possibility of other problems,
including CNS lymphomas.
Cryptosporidium
Cryptosporidium is a unicellular coccidian parasite that produces a
self-limited diarrhea in animals, travelers, and veterinarians. In AIDS
patients, infection instead produces sustained, profuse diarrhea, often
associated with malnutrition, malabsorption, and significant weight loss
(Soave et al., 1984~. Organisms are occasionally found in the lungs or
gallbladder. Recognition of Cryptosporidium in stool requires special
techniques.
No effective therapy for Cryptosporidium infection has been found in
animal studies or human clinical trials to date. Drugs found ineffective
include trimethoprim-sulfamethoxazole, iodoquinol, metronidazole, quin-
acrine, pentamidine, paramomycin, and tetracycline. Occasional clinical
or parasitologic response to furazolidone have been encountered, but
relapse occurs. Spiramycin, a macrolide antibiotic not commercially
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284 APPENDIX A
available in the United States with an antimicrobial spectrum similar to
that of erythromycin, has been reported to be effective in uncontrolled
trials (Collier et al., 1984), but this was not substantiated in one controlled
trial. Further controlled studies of this agent are under way. DEMO has
been used with differing results (Soave et al., 1985), though bone marrow
toxicity, especially thrombocytopenia, has been commonly noted
(Rolston et al., 19851.
Isospora belli
Isospora bell), another invasive coccidian parasite, produces a severe
diarrhea clinically indistinguishable from that caused by Cryptosporidium
in patients with AIDS (Whiteside et al., 19841. Oocysts are large but may
evade detection in stool examination, even with special techniques.
Trimethoprim-sulfamethoxazole or furazolidone were reported to be
effective in a few cases, but relapse occurred after discontinuation
(Westerman and Christensen, 19791.
Fungal Infections
Candida
Oral candidiasis (also known as thrush) is a very common infection in
people with AIDS and at high risk for AIDS. The presence of thrush in
high-risk patients without AIDS is strongly predictive of the subsequent
development of a serious opportunistic infection (i.e., the development of
AIDS) (Klein et al., 19841. However, only invasive esophageal candi-
diasis meets the Centers for Disease Control (CDC) surveillance defini-
tion of AIDS (see Appendix E).
There have been no treatment trials for either thrush or Candida
esophagitis in AIDS, so treatment recommendations must be based on
clinical experience and the results of treatment trials in other im-
munocompromised populations. Clotrimazole is commonly used to treat
oral candidiasis in immunosuppressed non-AIDS patients and has been
shown to be superior to placebo. Nystatin, the agent most commonly
employed in patients who are not immunocompromised, has been only
marginally effective in immunocompromised hosts.
Candida esophagitis may be asymptomatic, and most, but not all,
patients will have thrush. Treatment options include nystatin and keto-
conazole. Candidemia is rarely encountered, but treatment would be no
different than that for other populations, using amphotericin B for
disseminated disease.
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APPENDIX A 285
Cryptococcus
The meninges are the sole site of cryptococcal infection in 75 percent of
the cases seen in AIDS patients, though simultaneous or isolated infec-
tions of the blood, lungs, or other sites occur (Zuger et al., 19861.
Cryptococcal antigen and/or culture are positive at the site of infection in
over 90 percent of patients. In meningitis, cerebrospinal fluid (CSF) is
otherwise normal in more than 50 percent of AIDS patients (Kovacs et
al., 1984), a much higher percentage than with non-AIDS patients with
cryptococcal meningitis.
There are no comparative trials of treatment for cryptococcal infections in
patients with AIDS. However, in small series evaluated retrospectively,
clinical failure and relapse are more frequent than in other immunosup-
pressed populations. In large, multicenter series evaluating treatment of
cryptococcal meningitis in non-AIDS patients, amphotericin B in combina-
tion with 5-fluorocytosine achieved a better rate of cure and faster CSF
sterilization than did amphotericin B alone given for a longer time.
Intravenous amphotericin B in combination with 5-fluorocytosine is the
standard initial therapy for cryptococcal infection in patients with AIDS.
Total doses administered vary widely, and dose does not appear to correlate
with outcome. A convenient oral therapy for suppression after initial
treatment and also for the treatment of isolated pulmonary Cryptococcus
infection is much needed. Ketoconazole alone or in combination with other
antifungal agents is efficacious in the laboratory and in animal studies.
However, prospective trials are needed to establish the role of ketoconazole
in the treatment of cryptococcal infection in patients with AIDS.
Bacterial Infections
Mycobacterium tuberculosis
Tuberculosis is seen with increasing frequency in groups at risk for
AIDS, typically preceding the actual diagnosis of AIDS by several
months (Louie et al., 19851. In Haitian patients infected with Myco-
bacterium tuberculosis, disseminated disease was found in 80 percent of
patients with AIDS, whereas it was found in 20 percent of infected
Haitians without AIDS (Pitchenik et al., 19841. Response to standard
antituberculosis therapy is usually good.
Mycobacterium avium-intracellulare
Mycobacterium avium-intracellulare is a frequent isolate in blood,
sputum, urine, and feces of AIDS patients and is found at multiple sites in
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2SS6 APPENDIX A
about half of AIDS patients in whom postmortem evaluation is done
(Zakowski et al., 19821. This infection is usually identified late in the
course of AIDS, in association with fever, wasting, and fatigue, but often
without the failure of specific organ systems despite their involvement.
Many other AIDS-related infections and/or neoplasms are often present
simultaneously.
In non-AIDS patients with Mycobacterium avium-intracellulare, dis-
semination is rare and treatment of pulmonary disease with multiple drugs
or surgery is sometimes elective. Most strains of the bacterium are
resistant to standard antituberculosis drugs. However, most isolates from
AIDS patients have demonstrated in vitro sensitivity to two experimental
agents: ansamycin, a rifamycin S derivative, and clofazimine, a dye
derivative used to treat leprosy. Various combination therapies are also
under evaluation, but further investigation of therapeutic agents is sorely
needed.
Since Mycobacterium tuberculosis is a treatable disease in patients
with AIDS and ARC, disseminated mycobacterial disease is probably
best treated initially with triple drug therapy until cultures are available.
If the patient has shown amelioration of systemic symptoms, some
physicians would maintain that fame regimen even if infection with
Mycobacterium avium-intracellulare is documented. Others would treat
with ansamycin with or without clofazimine, and still others would try
four to six drugs chosen from INH, rifampin, ethambutol, an injectable
aminoglycoside, ethionamide, and cycloserine. More specific recommen-
dations cannot be made at this time. If the patient is premorbid or is
asymptomatic, many would recommend no treatment to avoid drug
toxicity. Pulmonary colonization alone does not necessitate treatment,
but close observation for potential disseminated infection is warranted.
Salmonella Infections
Several recent reports have disclosed 14 cases of bacteremic Salmo-
nella infections in AIDS and ARC patients. In the cases in New York and
Washington, D.C., all were due to Salmonella typhimurium, an infre-
quent cause of Salmonella sepsis in other populations. Infections were
severe, with sustained stool carriage and recurrent septicemia in some
patients, despite therapy with antibiotics to which the organisms were
sensitive in vitro (Glaser et al., 1985; Jacobs et al., 1985; Smith et al.,
1985).
In California, five cases of Salmonella dublin, a Salmonella species
closely linked to dairy cattle products such as raw milk, have been
reported in AIDS patients. Recurrent bacteremia has been the rule with
this infection as well.
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APPENDIX A 287
Pyogenic Bacteria
Pyogenic infections are relatively uncommon in AIDS patients but do
contribute to morbidity and mortality. Serious pneumococcal infections
may be more common in AIDS patients than in the hospital population at
large, and failure to respond to pneumococcal vaccine has been docu-
mented.
Viral Infections
Herpes Simplex Virus
A severe cutaneous herpes simplex virus (HSV) infection that persists
for more than four weeks is considered diagnostic of AIDS. Such an
infection may occur initially or be an ongoing problem throughout the
course of an AIDS illness. Other identified types of herpes infections
include severe orofacial herpes, encephalitis, myelitis, and pneumonia.
There are neither studies of the natural history nor comparative
treatment trials of these viral infections in AIDS or ARC. Acyclovir used
topically, intravenously, and orally reduces viral shedding and enhances
the healing of cutaneous lesions in other immunocompromised popula-
tions (Epstein, 19831. Oral and intravenous acyclovir are also effective
prophylaxes against recurrence in immunocompromised patients.
Herpes Zoster
Localized cutaneous zoster (shingles) is frequently encountered in
patients with AIDS and ARC. However, there are no natural history
studies of the relative severity of disease, the frequency of dissemination,
or the incidence of postherpetic neuralgia. Disseminated disease and
zoster encephalitis have been encountered.
Since most AIDS patients with herpes zoster are not sick enough to
warrant hospitalization, treatment with intravenous acyclovir is best
reserved for patients with cutaneous or visceral dissemination or systemic
symptoms.
Cytomega1/ovirus
Serologic evidence of cytomegalovirus (CMV) infection is almost
universal in homosexual men with AIDS and ARC. At bronchoscopy,
more than one-third of patients have evidence of colonization by CMV,
although histologic evidence of invasive disease is rare. In a small
prospective study, the presence of CMV had no effect on the survival of
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288 APPENDIX A
AIDS patients with Pneumocystis carinii. CMV can be associated with
symptomatic retinitis, adrenalitis, colitis, and encephalitis.
To date no commercially available therapies are effective. A nucleoside
analog, dihydroxymethyl propoxymethylguanine, has excellent in vitro
activity against replication of CMV. The drug is currently undergoing
clinical trials in AIDS patients, and preliminary results are encouraging
(Bach et al., 1985; Felsenstein et al., 1985; Masur et al., 19861.
Other Infections in Members of Risk Groups
Given the large number of people in the United States infected with
HIV, infections other than those considered diagnostic of AIDS are
certain to occur. It can be very difficult to establish a direct relationship
between these other medical problems and HIV-induced immune defi-
ciency. This is especially so with certain infectious diseases that were
well known to occur in members of AIDS risk groups prior to the
introduction of HIV in those communities. In the case of IV drug users,
these diseases are principally hepatitis B virus infection and endocarditis
from a variety of organisms. So far, clinical or laboratory patterns of these
infections and their response to conventional therapy do not seem to have
changed.
Like IV drug users, homosexual and bisexual men have frequently been
affected by infectious diseases. For example, they have a high incidence
of sexually transmitted diseases (Rein, 1986), including gonorrhea, syph-
ilis, genital herpes virus infections, genital warts, and bacterial and
parasitic infections of the large bowel (Quinn, 19861. Although changes in
life-styles of homosexual men in response to the AIDS epidemic have
reduced the frequency of new diagnoses of sexually transmitted diseases
in this group in recent years, they remain common.
Apart from sexually transmitted diseases such as persistent genital
HSV infection, the relationship of other common infections to underlying
cellular immune deficiency is unclear. In some instances, however, the
features of such infections are suspected of having changed in people
infected with HIV. Salmonellosis, for example, while not previously
uncommon in homosexual men, is nonetheless being seen with increased
incidence. In contrast to previous experience, it is increasingly resistant
to drug therapy and typified by frequent relapses. Although evidence is
still lacking, the fear remains that the delta agent may spread more readily
in both homosexual men and IV drug users, given established chronic
cases of hepatitis B and cellular immune deficiency.
Because infectious diseases are a common feature of at least two of the
major AIDS risk groups independent of the AIDS epidemic, it may be
extremely difficult to establish any direct connection between HIV
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APPENDIX A 289
i]
nfection and these other infections. Nevertheless, surveillance mecha-
nisms should continue to record these other infections, particularly to find
any evidence suggesting alterations in their clinical presentation or
response to therapy.
MALIGNANCIES AND OTHER NEOPLASTIC DISEASES
Kaposi's Sarcoma
Before 1981, Kaposi's sarcoma was a distinctly uncommon cancer in
the United States, and it had not previously been seen in healthy young
adults. Its recognition in young homosexual men in mid- 1981 was
therefore an early and obvious alert that a new disease had arrived.
Today, Kaposi's sarcoma remains a common and vie reminder of
AIDS.
~.. ~ I-~1A _;- ~+
Throughout the AIDS epidemic, Kaposi's sarcoma has played an
important role as an easily monitored clinical marker of the underlying
immune deficiency. For this reason, plus the fact that Kaposi's sarcoma
patients are frequently less severely immunocompromised than other
AIDS groups, Kaposi's sarcoma has been the focus of many clinical
therapy trials.
Kaposi's Sarcoma in Non-AIDS Populations
Prior to 1981, Kaposi's sarcoma, when seen, was limited to several
groups, including elderly American men (especially those of Mediterra-
nean descent), black Africans, and individuals with severe exogenous
immunosuppression such as renal allograft recipients. While reports of
Kaposi's sarcoma therapy in the elderly and African groups have little
relevance to current cases in AIDS patients, Kaposi's sarcoma in renal
transplant patients mimics the disease in AIDS patients. In both, Kaposi's
sarcoma is often, though not always, an aggressive malignancy with
extensive visceral spread; in both, opportunistic infections are common.
Perhaps the most striking observation, however, is that in renal allograft
patients Kaposi's sarcoma often regresses completely after the with-
drawal of immunosuppressive drugs. This suggests that in AIDS-related
Kaposi's sarcoma, drug-induced immune restoration might control the
cancer. It also implies that Kaposi's sarcoma may, in the future, be useful
as a clinical marker of the response to immunologic therapy.
Not all groups of AIDS patients are at equal risk of developing Kaposi's
sarcoma. For reasons as yet unclear, Kaposi's sarcoma is much more
frequent in homosexual men than in other AIDS patients (Cohn and
Judson, 1984; Des Jarlais et al., 19841. Infection of homosexuals with
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APPENDIX A 293
Toxoplasmosis, which was previously a rare opportunistic infection of the
brain, is frequently seen in AIDS patients, where it appears as multiple
abscesslike lesions. Cryptococcal meningitis is the second most common
opportunistic infection of the central nervous system in AIDS and is most
commonly seen in Africa. Disseminated herpesvirus infections of the
nervous system (herpes simplex, varicella poster, and cytomegalovirus)
are seen less commonly. Progressive multifocal leukoencephalopathy, an
otherwise rare demyelinating disease caused by papovavirus infection of
oligodendrocytes, has occurred in patients with unprecedented fre-
quency. A variety of other bacterial, viral, and fungal infections have also
been reported (Snider et al., 19831.
Tumors of the central nervous system in patients with AIDS have
largely been primary CNS lymphomas. Secondary lymphomas and met-
astatic Kaposi's sarcoma have occurred much more rarely. Metabolic
encephalopathies associated with pulmonary, hepatic, and renal failure
are found postmortem in approximately 10 percent of AIDS patients
(Navia et al., 19861.
Although many of these infections and tumors have unusual presenta-
tion, five years of experience with AIDS have sharpened clinical evalu-
ations and diagnoses and have allowed more timely and effective treat-
ments, particularly for toxoplasmosis and cryptococcal meningitis.
Aseptic Meningitis
Healthy seropositive persons and ARC patients sometimes experience
a self-limited aseptic meningitis. Though of minor clinical importance,
this illness may have major significance in relation to disease pathogen-
esis. On several occasions, it has been noted at the time of seroconver-
sion, and the virus has been isolated from cerebrospinal fluid (Cooper et
al., 1985; Ho et al., 1985~. Symptoms include fever, headache, meningeal
signs, and in some cases cranial nerve palsies. Cerebrospinal fluid shows
a mononuclear cell pleocytosis and protein elevation. This may represent
HIV's initial invasion of the central nervous system. The frequency of its
subclinical occurrence in HIV-infected persons is not known.
Subacute Encephalitis
Dementias that are sufficient to be detected by objective psychological
tests and that are associated with subacute encephalitis appear to occur in
over 50 percent of patients with AIDS. In a New York study, after
excluding patients with metabolic encephalopathies and opportunistic
infections, 46 of 70 AIDS patients had clinical evidence of dementia. This
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294 APPENDIX A
correlated with the severity of the subacute encephalitis found at autopsy
in over 80 percent of the cases (Navia et al., 19861.
In the majority of cases, the cerebrospinal fluid shows an elevation of
protein and mild pleocytosis with a striking reversal of the CD4 to CD8
ratio. Computerized tomography shows cortical atrophy and enlarged
ventricles. Magnetic resonance imaging, which has been limited, may
show remarkable white matter abnormalities. Multiple abnormal signals
from white matter have been seen even in ambulatory, minimally affected
patients. A diffuse abnormal signal in white matter may be present in
patients with full-blown dementia.
Despite the severity of clinical disease and the dramatic findings on
imaging studies, histopathologic changes are remarkably subtle. There is
a diffuse pallor of white matter, perivascular infiltrations of lymphocytes
and macrophages, and, in more advanced cases, multinucleated cells.
These pathologic changes have been noted to be most striking in the white
matter, basal ganglia, and temporal areas (Navia et al., 1986~.
The dementia in children born with lIIV infection frequently shows a
more striking clinical course and pathology. During early development,
they fail to thrive, develop microcephaly, and suffer from seizures,
blindness, and abnormal movements. Their brains show decreased vol-
ume with gross atrophy, many microglial nodules and multinucleated cells
in the white matter, and vascular calcifications (Epstein et al., 1985b;
Sharer et al., 19861.
Myelopa thy
Vacuolar myelopathy is found in approximately 20 percent of patients
with AIDS. Clinically, this correlates with the development of progres-
sive paraparesis accompanied by ataxia, spasticity, and incontinence.
Pathologic vacuolar degeneration of myelin is found in the dorsal and
lateral columns without inflammation (Petito et al., 19851.
Peripheral tieuropathies
Involvement of the peripheral nervous system takes three forms in
AIDS. Many patients develop a severe painful sensory neuropathy with
electrophysiologic characteristics indicative of axonal degeneration. The
pathology of this neuropathy is undefined but may involve dorsal root
ganglia. A second painful, less common multifocal neuropathy appears to
be related to a vasculitis with multifocal nerve infractions. This has been
found in patients with both AIDS and ARC.
Third, a group of patients, none with AIDS but seropositive and often
with various signs of ARC, have developed acute or subacute demyelinat
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APPENDIX A 295
ing neuropathies resembling Guillain-Barre syndrome. These patients
have been found to recover spontaneously or may respond to plasma-
pheresis. This has been postulated to represent an autoimmune phenom-
enon during a time of immunologic deregulation occurring prior to the
onset of clinically apparent immunosuppression as manifested in clinical
AIDS. In addition to the demyelination normally seen in the Guillain-
Barre syndrome, this disease shows a strikingly greater degree of inDam-
mation and vacuolar changes in cells than is the case with usual demy-
elinating neuropathies (Cornblath et al., in press).
HIV Infection of the Nervous System
HIV has been isolated from the nervous systems of AIDS and ARC
patients with necrologic syndromes with remarkable consistency. Levy et
al. (1985) recovered virus from the spinal fluid of 13 of 14 AIDS or ARC
patients, including one without necrologic symptoms. Ho et al. (1985)
recovered virus from at least one spinal fluid or tissue specimen from 24
of 33 AIDS patients. These specimens included spinal fluid isolates from
6 of 7 patients with chronic meningitis, the brains of 6 patients with
dementias, the spinal cord of one patient with myelopathy, the spinal fluid
from one patient who had an acute meningitis at the time of seroconver-
sion, and a peripheral nerve of one patient with demyelinating neu
ropathy.
Further evidence for the direct replication of HIV in the brain comes
from the demonstration of intrathecal antibody synthesis in patients.
Comparisons of antibody levels in serum and in cerebrospinal fluid
indicate antigenic stimulation within the nervous system (Resnick et al.,
1985).
Initial in situ hybridization studies have also demonstrated that cells
within the microglial nodules contain the RNA from HIV. Viral DNA
sequences have also been found in brains by Southern blot analysis,
where they occurred in greater quantities than in the spleen, lymph nodes,
liver, or lung (Straw et al., 19851.
These findings establish that the virus is present in the nervous system
and that its presence correlates to some degree with necrologic disease.
They fail to identify, however, whether the virus is in neural cells or in
cells of hematogenous origin within the brain (Johnson and McArthur,
19861.
Cellular Localization of HIV
Electron microscope studies have demonstrated apparent virus parti-
cles within multinucleated cells, probably of macrophagic origin. In one
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296 APPENDIX A
case, particles resembling virus were also seen within astrocytes, but the
failure to find budding particles leaves open the possibilities that these
were phagocytosed (Epstein et al., 1985a).
A variety of studies have now been done with immunocytochemical
staining for viral antigen, followed by double staining to identify cells with
cell markers or in situ hybridization. In summary, all have shown low
numbers of infected cells and a predominance of viral antigens and viral
nucleic acids in macrophages within perivascular inflammatory responses
(Gabuzda et al., in press; Koenig et al., 1986; Pumarola-Sune et al., in
press; Wiley et al., in press). Several of these studies note that the
presence of the virus in perivascular cells is more prominent in the white
matter. Most of these studies have also found some infected parenchymal
cells.
The most interesting and disparate findings are those of Wiley et al. (in
press), who used immunocytochemistry together with in situ hybridiza-
tion to find involvement in 9 of 12 cases of capillary vascular endothelial
cells of the brain. This finding could be of major importance in terms of
the virus's mode of entry, the potential pathogenesis of the diffuse white
matter lesions, and the development of future therapeutic strategies.
Studies by Pert (1986) have attempted to map CD4 cell receptors in the
brain of humans, monkeys, and rats. She has found the antigen to be
predominantly in the outer layers of the cortex and in the hippocampus.
The presence of these receptors is interesting, but their location fails to
correlate with that of the histopathologic distribution of the viral antigens.
Unsolved Problems
The timing and frequency of nervous system infection by HIV is not
known. The isolations of HIV with aseptic meningitis at the time of
seroconversion raise the grim possibility that the virus may invade the
nervous system very early in many patients. This is reminiscent of
syphilis, where pathogenic organisms may invade the nervous system
early but remain latent until disease develops up to 30 years later.
How much time elapses between involvement of the central nervous
system and the development of the subacute encephalitis with dementia
also remains unknown. Clearly, this has broad implications for the use of
therapeutic immunomodulators, which could improve hematologic pa-
rameters and clear systemic infections but have little effect on an ongoing
or latent infection within the central nervous system. It also has major
implications for the use of drug therapies. If vascular endothelial cells are
the primary site of infection, the systemic administration of drugs may be
effective; if rare neurons or glial cells are involved, it may not.
The pathogenesis of the CNS lesions is also mysterious. Imaging
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APPENDIX A 297
studies suggest widespread severe white matter disease, but the histologic
findings are subtle and the number of cells with evidence of HIV infection
is very small. This does not appear to be analogous either to acute
infections such as poliomyelitis, where selective infection of specific cells
(the motor neurons) leads to paralysis, or to chronic infections such as
progressive multifocal leukoencephalopathy, where oligodendrocytes
harbor vast amounts of replicated papovavirus and are lysed, causing
demyelinating disease. Instead, complex and indirect pathogenic mecha-
nisms may be involved. For instance, recent studies of visna virus
(Kennedy et al., 1986; Narayan et al., 1985) suggest that small amounts of
visna virus in rare macrophages can cause the induction of a novel
interferon, which in turn induces the expression of an Ia antigen on neural
cells. This then evokes an inflammatory and demyelinating disease,
despite a paucity of virus.
PEDIATRIC AIDS
Clinical Features and Diagnosis
The clinical manifestations of AIDS in children are significantly dif-
ferent from those in adults. In one series they included failure to thrive (65
percent), recurrent bacterial infections (43 percent), persistent candidiasis
(70 percent), generalized lymphadenopathy (74 percent), recurrent (31
percent) or protracted (33 percent) diarrhea, hepatosplenomegaly,
lymphadenopathy, parotitis (14 percent), interstitial pneumonitis (59
percent), chronic otitis media (48 percent), and encephalopathy. Kaposi's
sarcoma (19 percent) and B-cell lymphoma occur but are less frequent
than in adults (Parks and Scott, 19861.
In a minority of infants the same types of infections are seen that have
been described in adults. Almost a third (32 percent) of AIDS cases in
children have Pneumocystis carinii pneumonia. Candida esophagitis
occurs in 22 percent of cases, and disseminated cytomegalovirus infection
is found in 24 percent. On the other hand, disseminated cytomegalovirus
was a well-known perinatally acquired infection before the emergence of
HIV and, therefore, is not very specific evidence of AIDS. Even though
Kaposi's sarcoma is found in some pediatric cases, the lesions are located
in lymph nodes as opposed to the skin in adults. The lesions are usually
found only at autopsy and thus are not of diagnostic help in caring for the
patient.
In general, pediatric AIDS is characterized by the occurrence of
unusually severe infections in a child without the presence of predispos-
ing factors, such as congenital immunodeficiency or antineoplastic che-
motherapy. Recurrent infection is by far the most frequent AIDS-related
OCR for page 298
298 APPENDIX A
syndrome in the pediatric age group. In addition to oral and esophageal
candidiasis resistant to the usual therapies and recurrent viral infections
(including herpetic stomatitis, varicella/herpes poster, condyloma, and
molluscum contagiosum), children frequently suffer from bacterial infec-
tions. In this regard, infections in children are different from those in
adults, in whom bacterial infections are much less frequent. Bacterial
infections seen include recurrent pneumonia, bacterial sepsis (especially
with Streptococcus pneumonias and Haemophilus influenzoe), and
chronic draining otitis media.
Infants who are born infected tend to be small for gestational age and are
usually symptomatic by six months of age. Recently, a specific phenotypic
appearance of young infants with AIDS has been described, which suggests
early in utero spread (Marion et al., 19861. Infants who are transfused with
contaminated blood during the first year of life may be clinically well from
one to four years before developing clinical symptoms.
Diagnostic Criteria
The conditions that have been listed above are similar to many that are
usual in the general pediatric practice. What is unusual is that these
problems are extremely severe and persistent in patients with AIDS.
Lymphadenopathy with associated failure to thrive appears to be the
most common finding.
Once the clinician's suspicion of the possible diagnosis of AIDS has
been aroused, the appropriate laboratory tests should be ordered. The
laboratory results will differ depending on whether they are performed
early (before there are definitive clinical findings) or late (after one or
more of the clinical findings previously described has occurred).
The earliest finding is that of a positive test for HIV antibodies, usually
made using the ELISA test. This result must be confirmed with the
Western blot test. Where the antibody test is positive, there is a very good
chance that the virus will be isolated. A common finding is a polyclonal
hypergammaglobulinemia, which results from increased stimulation of B
cells and/or decreased suppression by T lymphocytes. Usually this
involves IgG, but sometimes also IgA and IgM. Some patients may have
hypogammaglobulinemia.
In the later stages of the disease, the laboratory findings are consistent
with a deterioration of T-lymphocyte function along with one or more of
the clinical syndromes already described and HIV positivity. Children
tend to have levels of lymphocytes higher than those seen in adults or
older patients, presumably because children normally have much higher
levels of lymphocytes than do adults. Special testing may reveal that CD4
cells have been depleted relative to CD8 cells, producing an inverted
OCR for page 299
APPENDIX A 299
T-lymphocyte subset ratio. This finding, in combination with polyclonal
increase in IgG levels, is sufficient for laboratory confirmation of a
tentative or presumptive diagnosis of AIDS in an infant.
In addition to n~ v, a variety of other viruses are often present,
including hepatitis B virus, cytomegalovirus, Epstein-Barr virus, and
DANA A4_~^~^V ~ ~ AN __ 7 _ J ~ ~
herpes simplex. When there is severe disease, there may oe a negative
HIV antibody test.
It is important to exclude other congenital immunodeficiency syn-
drc~mes. such as the Nezelof syndrome or combined immune deficiency
,
my. .. .- ~ 1 ._ ~ _1~ 1 =_1:~ LEA 1~,
syndrome. 'line combination OI selected cllnlt;~ ~;~ Beau ~a~l"~l,
results provides the physician with a presumptive diagnosis of AIDS in
infants. But it has become clear that it is impractical to try to make the
diagnostic criteria for AIDS in children fit those of adults. It seems that
grouping the clinical findings into different syndromes may be the most
elective way to recognize clinical AIDS when Kaposi's sarcoma and
opportunistic infections do not occur. Because most clinicians still try to
use the adult diagnostic criteria to diagnose AIDS in small children, this
disorder is underreported in the pediatric age group. Additional work is
needed to further clarify the natural history of AIDS in children.
REFERENCES
Bach, M. C., S. P. Bagwell, N. P. Knapp, K. M. Davis, and P. S. Hedstron. 1985.
9-(1,3-Dihydroxy-2-propoxymethyl)guanine for cytomegalovirus infections in patients
with the acquired immunodeficiency syndrome. Ann. Intern. Med. 103:381-382.
Bigby, T. D., D. Margolskee, J. L. Curtis, P. F. Michael, D. Sheppard, W. K. Hadley, and
P. C. Hopewell. 1986. The usefulness of induced sputum in the diagnosis of Pneumocystis
carinii pneumonia in patients with the acquired immunodeficiency syndrome. Am. Rev.
Respir. Dis. 133:515-518.
Broaddus, C., M. D. Dake, M. S. Stulbarg, W. Blumenfeld, K. Hadley, J. A. Golden, and
P. C. Hopewell. 1985. Bronchoalveolar ravage and transbronchial biopsy for the diagnosis
of pulmonary infections in the acquired immunodeficiency syndrome. Ann. Intern. Med.
102:747-752.
Catterall, J. R., I. Potasman, and J. S. Remington. 1985. Pneumocystis carinii pneumonia in
the patient with AIDS. Chest 88:758-762.
Cohn, D. C., and F. N. Judson. 1984. Absence of Kaposi's sarcoma in hemophiliacs with
AIDS. N. Engl. J. Med. 101:401.
Collier, A. C., R. A. Miller, and J. D. Meyers. 1987. Cryptosporidiosis after marrow
transplantation: Person-to-person transmission and treatment with spiramycin. Ann.
Intern. Med. 101:205-206.
(banner n A.. J. Gold P. Maclean, B. Donovan, R. Finlayson, T. G. Barnes, H. M.
~~~r~
Michelmore, P. I3rooke, and x. Penny. EYES. ACule Al~O r~-vV1tU~ i~il~tlvll. ~llill~lVI'
of a clinical illness associated with seroconversion. Lancet 1:537-540.
Cornblath, D. R., J. C. McArthur, and J. W. Griffin. In press. Inflammatory demyelinating
peripheral neuropathies associated with AIDS retrovirus infection. Ann. Neurol.
Des Jarlais, D. C., M. Marmor, P. Thomas, M. Chamberland, S. Zolla-Pazner, and D. J.
OCR for page 300
300 APPENDIX A
Sencer. 1984. Kaposi's sarcoma among four different AIDS risk groups. N. Engl. J. Med.
310:1119.
Drew, W. L., R. C. Miner, J. C. Ziegler, J. H. Gullett, D. I. Abrams, M. A. Conant, E.-S.
Huang, J. R. Groundwater, P. Volberding, and L. Mintz. 1982. Cytomegalovirus and
Kaposi's sarcoma in young homosexual men. Lancet II:125-127.
Epstein, E. 1983. Acyclovir for immunocompromised patients with herpes zoster. N. Engl.
J. Med. 309:1254.
Epstein, L. G., L. R. Sharer, E.-S. Cho, M. Myerhofer, B. A. Navia, and R. W. Price.
1985a. HTLV-III/LAV-like retrovirus particles in the brains of patients with AIDS
encephalopathy. AIDS Res. 1:447-454.
Epstein, L. G., L. R. Sharer, V. V. Joshi, M. M. Fojas, M. R. Koenigsberger, and J. M.
Oleske. 1985b. Progressive encephalopathy in children with acquired immunodeficiency
syndrome. Ann. Neurol. 17:488-496.
Felsenstein, D., D. J. D'Amico, M. S. Hirsch, D. M. Cederberg, P. de Miranda, and R. T.
Schooley. 1985. Treatment of cytomegalovirus retinitis with 9-[2-hydroxy-1-(hydroxy-
methyl)ethoxymethyl]guanine. Ann. Intern. Med. 103:377-380.
Gabuzda, D. H., D. D. Ho, S. M. de al Monte, M. S. Hirsch, T. R. Rota, and R. A. Sobel.
In press. Immunohistochemical identification of HTLV-III antigen in brains of patients
with AIDS. Ann. Neurol.
Glaser, J. B., L. Morton-Kute, S. R. Berger, J. Weber, F. P. Siegel, C. Lopez, W. Robbins,
and S. H. Landesman. 1985. Recurrent Salmonella typhimurium bacteremia associated
with the acquired immunodeficiency syndrome. Ann. Intern. Med. 102:189-193.
Gordin, F. M., G. L. Simon, C. B. Wofsy, and J. Mills. 1984. Adverse reactions to
trimethoprim-sulfamethoxazole in patients with AIDS. Ann. Intern. Med. 100:495-499.
Haverkos, H. W. 1984. Assessment of therapy for Pneumocystis carinii pneumonia. Am. J.
Med. 76:501-508.
Ho, D. D., T. R. Rota, R. T. Schooley, J. C. Kaplan, J. D. Allan, J. E. Groopman, L.
Resnick, D. Felsenstein, C. A. Andrews, and M. C. Hirsch. 1985. Isolation of HTLV-III
from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related
to the acquired immunodeficiency syndrome. N. Engl. J. Med. 313:1493-1497.
Hughes, W. T., and B. C. Smith. 1984. Efficacy of diaminodiphenylsulfone and other drugs
in murine Pneumocystis carinii pneumonia. Antimicrob. Agents Chemother. 26:436.
Hughes, W. T., S. Feldman, S. C. Chaudhary, M. J. Ossi, F. Cox, and S. K. Sanyal. 1978.
Comparison of pentamidine isothionate and trimethoprim-sulfamethoxazole in the treat-
ment of Pneumocystis carinii pneumonia. J. Pediatr. 92:285-291.
Ioachim, H. C., M. C. Cooper, and G. C. Hellman. 1985. Lymphomas in men at high risk for
acquired immune deficiency syndrome (AIDS). A study of 21 cases. Cancer 56:2831-2842.
Jacobs, J. L., M. W. M. Gold, H. W. Murray, R. B. Roberts, and D. Armstrong. 1985.
Salmonella infections in patients with the acquired immunodeficiency syndrome. Ann.
Intern. Med. 102:186-188.
Johnson, R. T., and J. C. McArthur. 1986. AIDS and the brain. Trends Neurosci. 9:91-94.
Kaplan, L. D., R. Wong, C. Wofsy, and P. A. Volberding. 1986. Trimethoprim-sulfa-
methoxazole (TMP-SMZ) prophylaxis of Pneumocystis carinii pneumonia (PCP) in AIDS.
P. 53 in Abstracts of the Second International Conference on AIDS, Paris, June 23-25,
1986.
Kennedy, P. G. E., O. Narayan, Z. Ghotbi, J. Hopkins, H. E. Gendelman, and J. E.
Clements. 1986. Persistent expression of Ia antigen and viral genome in visna-maedi
virus-induced inDammatory cell s . J. . Exp . Med. . 162: 1970- 1982.
Klein, R. S., C. A. Harris, C. B. Small, B. Moll, M. Lesser, and G. H. Friedland. 1984. Oral
candidiasis in high risk patients as the initial manifestation of the acquired immunodefici-
ency syndrome. N. Engl. J. Med. 311:354-358.
OCR for page 301
APPENDIX A 30)
Koenig, S., H. E. Gendelman, M. C. DelCanto, M. Yungbluth, G. H. Pezeskpour, T. Folks,
M. Martin, H. C. Lance, and A. S. Fauci. 1986. Detection of AIDS retroviral RNA in
nonlymphoid cells in the brain of an AIDS patient with encephalopathy. Clin. Res. 34:722A.
Kovacs, J. A., J. W. Hiemenz, A. M. Macher, D. Stover, H. W. Murray, J. Shelhamer, H.
C. Lane, C. Urmacher, C. Honig, D. L. Longo, M. M. Parker, C. Natanson, J. E.
Parrillo, A. S. Fauci, P. A. Pizzo, and H. Masur. 1984. Pneumocystis carinii pneumonia:
A comparison between patients with acquired immunodeficiency syndrome and patients
with other immunodeficiencies. Ann. Intern. Med. 100:663-671.
Levy, J. A., J. Shimabukuro, H. Hollander, J. Mills, and L. Kaminsky. 1985. Isolation of
AIDS-associated retrovirus from cerebrospinal fluid and brains of patients with neuro-
logical symptoms. Lancet II:586-588.
Lou~e, E., L. B. Rice, and R. S. Holzman. 1985. Mycobacterium tuberculosis (Mtb)
infection in patients with AIDS. P. 38 in Abstracts of the International Conference on
AIDS, Atlanta, Gal, April 14-17, 1985.
Luft, B. J., R. G. Brooks, F. K. Conley, R. E. McCabe, and J. S. Remington. 1984.
Toxoplasmic encephalitis in patients with acquired immune deficiency syndrome. JAMA
252:913-917.
Marion, R. W., A. A. Wiznia, G. Hutcheon, and A. Rubenstein. 1986. Human T-cell
lymphotropic virus type III (HTLV-III/LAV) embryopathy. A new dysmorphic syndrome
associated with intrauterine HTLV-III infection. Am. J. Dis. Child. 140:638-640.
Marmor, M., A. E. Friedman-Kien, L. Laubenstein, R. D. Byrum, D. C. William, S.
D'Onofrio, and N. Dubin. 1982. Risk factors for Kaposi's sarcoma in homosexual men.
Lancet 1:1083-1087.
Masur, M., H. C. Lane, and A. Palestine. 1986. Effect of 9-(1,3-dihydroxy-2-propoxy-
methyl) guanine on serious cytomegalovirus disease in eight immunosuppressed homo-
sexual men. Ann. Intern. Med. 104:41-44.
Mintzer, D. M., F. X. Real, L. Jovino, and S. E. Krown. 1985. Treatment of Kaposi's
sarcoma and thrombocytopenia with vincristine in patients with the acquired im-
munodeficiency syndrome. Ann. Intern. Med. 102:200-202.
Mitsuyasu, R. T., and J. E. Groopman. 1984. Biology and therapy of Kaposi's sarcoma.
Semin. Oncol. 11:53-59.
Narayan, O., D. Sheffer, J. E. Clements, and G. Tennekoon. 1985. Restricted replication of
lentiviruses: Visna viruses induce a unique interferon during interaction between lym-
phocytes and infected macrophages. J. Exp. Med. 162:1954-1969.
Nash, G., and S. Fligiel. 1984. Pathologic features of the lung in the acquired immune
deficiency syndrome (AIDS): An autopsy study of seventeen homosexual males. Am. J.
Clin. Pathol. 81:6-12.
Navia, B. A., E.-S. Cho, C. K. Petito, and R. W. Price. 1986. The AIDS dementia complex:
II. Neuropathology. Ann. Neurol. 19:525-535.
Ognibene, F. P., J. Shelhamer, V. Gill, A. M. Macher, D. Loew, M. M. Parker, E.
Gelmann, A. S. Fauci, J. E. Parrillo, and H. Masur. 1984. The diagnosis of Pneumocystis
carinii pneumonia in patients with the acquired irnmunodeficiency syndrome using
subsegmental bronchoalveolar ravage. Am. Rev. Respir. Dis. 129:929-932.
Parks, W. P., and G. B. Scott. 1986. An Overview of Pediatric AIDS: Approaches to
Diagnosis and Outcome Assessment. Background paper. Washington, D.C.: Committee
on a National Strategy for AIDS.
Pert, C. B. 1986. HTLV-III virus visualization of the OKT4 antigen in brain. Paper
presented at the National Institute of Mental Health AIDS Conference. Bethesda, Md.
Petito, C. A., B. A. Navia, E.-S. Cho, B. D. Jordan, D. C. George, and R. W. Price. 1985.
Vacuolar myelopathy pathologically resembling subacute combined degeneration in
patients with the acquired immunodeficiency syndrome. N. Engl. J. Med. 312:874-879.
OCR for page 302
302 APPENDIX A
Pitchenik, A. E., C. Cole, B. W. Russet, M. A. Fischl, T. J. Spira, and D. E. Snider, Jr.
1984. Tuberculosis, atypical mycobacteriosis and the acquired immunodeficiency syn-
drome among Haitian and non-Haitian patients in south Florida. Ann. Intern. Med. 101:
641-645.
Pumarola-Sune, T., B. A. Navia, C. Cordon-Cardo, E.-S. Cho, and R. W. Price. In press.
LAV/HTLV-III antigen in the brains of patients with the AIDS dementia complex.
Quinn, T. C. 1986. Clinical approach to intestinal infections in homosexual men. Med. Clin.
North Am. 70:611-634.
Rein, M. F. 1986. Clinical approach to urethritis, mucocutaneous lesions, and inguinal
lymphadenopathy in homosexual men in AIDS and other medical problems in the male
homosexual. Med. Clin. North Am. 70:587-609.
Resnick, L., F. diMarzo-Veronese, J. Schupbach, W. W. Tourtellotte, D. D. Ho, F. Muller,
P. Shapshak, M. Vogt, J. E. Groopman, P. D. Markham, and R. C. Gallo. 1985.
Intra-blood-brain-barrier synthesis of HTLV-III specific IgG in patients with necrologic
symptoms associated with AIDS or AIDS-related complex. N. Engl. J. Med. 313:1498-
1504.
Rolston, K., V. Fainstein, P. Mansell, A. Sjoerdsma, and G. P. Bodey. 1985. Alpha-
difluoromethylornithine (DEMO) in the treatment of cryptosporidiosis in AIDS patients:
Preliminary evaluation. P. 77 in Abstracts of the International Conference on AIDS,
Atlanta, Gal, April 14-17, 1985.
Schoeppel, S. C., R. T. Hoppe, R. F. Dorfman, S. J. Horning, A. C. Collier, T. G. Chew,
and L. M. Weiss. 1985. Hodgkin's disease in homosexual men with generalized
lymphadenopathy. Ann. Intern. Med. 102:68-70.
Sharer, L. R., L. G. Epstein, E.-S. Cho, V. V. Joshi, M. F. Myenhofer, L. F. Rankin, and
C. K. Petito. 1986. Pathology of AIDS encephalopathy in children: Evidence for
LAV/HTLV-III infection in brain. Human Pathol. 17:271-284.
Shaw, G. M., M. E. Harper, B. H. Hahn, L. G. Epstein, D. C. Gajdusek, R. W. Price, B.
A. Navia, C. K. Petito, C. J. O'Hara, E.-S. Cho, J. M. Oleske, F. Wong-Staal, and R. C.
Gallo. 1985. HTLV-III infection in brains of children and adults with AIDS encephalop-
athy. Science 227:177-182.
Smith, P. D., A. M. Macher, M. A. Bookman, R. V. Boccia, R. G. Steis, V. Gill, J.
Manischewitz, and E. P. Gelmann. 1985. Salmonella typhimurium enteritis and bac-
teremia in the acquired immunodeficiency syndrome. Ann. Intern. Med. 102:207-209.
Snider, W. D., D. M. Simpson, G. Nielson, J. W. M. Gold, C. Metroka, and J. B. Posner.
1983. Neurologic complications of acquired immunodeficiency syndrome: Analysis of 50
patients. Ann. Neurol. 14:403-418.
Soave, R., R. L. Danner, C. L. Honig, P. Ma, C. C. Hart, T. Nash, and R. B. Roberts. 1984.
Cryptosporidiosis in homosexual men. Ann. Intern. Med. 100:504-511.
Soave, R., A. Sjoerdsma, and M. J. Cawein. 1985. Treatment of cryptosporidiosis in AIDS
patients with alpha-difluoromethylornithine. P. 77 in Abstracts of the International
Conference on AIDS, Atlanta, Gal, April 14-17, 1985.
Volberding, P. A., R. Valero, J. Rothman, and G. Gee. 1984. Alpha interferon therapy of
Kaposi's sarcoma in AIDS. Ann. N.Y. Acad. Sci. 437:439-446.
Westerman, E. L., and R. P. Christensen. 1979. Chronic Isospora belli infection treated
with co-trimoxazole. Ann. Intern. Med. 91:413-414.
Whiteside, M. E., J. S. Barkin, R. G. May, S. D. Weiss, M. A. Fischl, and C. L. MacLeod.
1984. Enteric coccidiosis among patients with the acquired immunodeficiency syndrome.
Am. J. Trop. Med. Hyg. 33:1065-1072.
Wiley, C. A., R. D. Schrier, J. A. Nelson, P. W. Lampert, and M. A. B. Oldstone. In press.
Cellular localization of human immunodeficiency virus infection within the brains of
acquired immunodeficiency syndrome (AIDS) patients. Proc. Natl. Acad. Sci. USA.
OCR for page 303
APPENDIX A 303
Wong, B., J. W. Gold, A. E. Brown, M. Lang, R. Fried, M. Grieco, D. Mildvan, J. Giron,
M. L. Topper, C. W. Lerner, et al. 1984. Central nervous system toxoplasmosis in
homosexual men and parenteral drug abusers. Ann. Intern. Med. 100:36-42.
Zakowski, P., S. Fligiel, G. W. Berlin, and L. Johnson, Jr. 1982. Disseminated Mycobac-
terium avium-intracellulare infection in homosexual men dying of acquired immunodefici-
ency syndrome. JAMA 248:2980-2982.
Ziegler, J. L., J. A. Beckstead, P. A. Volberding, D. I. Abrams, A. M. Levine, R. J. Lukes,
P. S. Gill, R. L. Burkes, P. R. Meyer, C. E. Metroka, J. Mouradian, A. Moore, S. A.
Riggs, J. J. Butler, F. C. Cabanillas, E. Hersh, G. R. Newell, L. J. Laubenstein, D.
Knowles, C. Odajnyk, B. Raphael, B. Koziner, C. Urmacher, and B. D. Clarkson. 1984.
Non-Hodgkin's lymphoma in 90 homosexual men. Relation to generalized lymphadeno-
pathy and the acquired immunodeficiency syndrome. N. Engl. J. Med. 311:565-570.
Zuger, A., E. Louie, R. S. Holtzman, M. S. Simberkoff, and J. J. Rahal. 1986. Cryptococcal
disease in patients with acquired immunodeficiency syndrome. Ann. Intern. Med. 104:
234-240.
Representative terms from entire chapter:
acquired immunodeficiency
