INTRODUCTION

AIDS in children has been a sensational but little understood issue. Fear and
ignorance have impeded efforts to understand and control the AIDS epidemic
in adults, and this has been even more true for children. Children acquire AIDS
as a consequence of adult behavior, but they nevertheless have shared general
public opprobrium frequently cast on affected patients.

As of 30 March 1987, a cumulative total of 471 children nationwide met the
strict criteria established by the Centers for Disease Control (CDC) for Acquired
Immunodeficiency Syndrome (AIDS) in children. An untold additional number,
perhaps two to three times more, are infected with the Human Immunodeficiency
Virus (HIV) but do not meet the CDC criteria. It is not generally appreciated
that AIDS is only one of the more severe manifestations of infection with HIV.
Other children infected with HIV may fall anywhere on a spectrum from being
completely asymptomatic through suffering growth and developmental retarda-
tion to having multisystem disease known as AIDS-Related Complex (ARC)
involving blood, skin, brain, heart, kidneys, and other organs.

Both future opportunities for control of HIV infection and the possibilities for
future disaster lie in the area of heterosexually transmitted infections in adults
and their consequences to children. At present, pediatric infections—other than
those acquired previously through HIV contaminated blood products —stem largely
from mothers who themselves are intravenous drug users or whose partners either
abuse drugs or are bisexual. If the virus continues to spread through these groups,
there inevitably will be more heterosexual infections and more transmission to
infants, both within and without the drug using and bisexual sectors.

The idea for this conference arose from our perception that the attention of
the nation needed to be focused on prevention of HIV infection in children and
on the difficulties of caring for those children already infected. At the same time,
we learned that the Surgeon General was considering convening a workshop specif-
ically to deal with issues arising from pediatric AIDS. Accordingly, a series of
meetings took place in the summer and fall of 1986 to plan for a conference.
In the subsequent months, approximately 200 people were invited to a closed
conference, known as the “Surgeon General’s Workshop on Children with HIV
Infection and Their Families.”

We made a deliberate effort to convene not only clinical and research physi-
cians, but other types of health providers, clergy, economists, educators, media
representatives, and parents. Due attention was given to ethnic and geographical
representation.

The workshop took place at Children’s Hospital of Philadelphia on 6-8 April,
1987. The fifteen papers surveying what is known in the field were presented
in plenary session. Following are abstracts of the papers presented in the plenary
sessions and summaries of the recommendations from the Work Groups.
The results set out in these pages exemplify a peculiarly American way of
problem-solving: to bring together the informed and the interested, to give each
a voice, and to form a consensus which avoids extremes.

We believe that these recommendations are both sound and urgent. If we can
learn how to deal humanely with HIV-infected children and to prevent new mothers
and children from becoming infected, there is still a chance of stopping the AIDS
epidemic. For this purpose, the energies of the American people will need to
be mobilized in a “moral equivalent of war” to fight against the spread of HIV.

Stanley A. Plotkin, M.D.

Director, Division of Infectious Diseases
The Children’s Hospital of Philadelphia
Professor of Pediatrics and Microbiology
University of Pennsylvania

Professor, The Wistar Institute
EXCERPT FROM KEYNOTE ADDRESS

C. Everett Koop, M.D., D.Sc.
Surgeon General, Public Health Service

Nearly five years ago I came to Philadelphia to stand before a similar group
of concerned Americans and share my concerns about handicapped children and
their families. My opening remarks at that Surgeon General's Workshop noted
that our task would not be easy. We were to consider very complex issues, such
as the emotional, the moral, the medical, the technological, the social, the psycho-
logical, and the financial issues associated with the care for handicapped children.
I also mentioned the awesome challenge of putting a dollar value on a human life.

I wish it were not so, but those remarks are just as appropriate today when
we consider yet another problem of major proportion to cope with: the conse-
quences of Human Immunodeficiency Virus (HIV) infection in children and adoles-
cents. Five years ago little was known about the nature and extent of AIDS. And
although we suspected that children would become involved, it was then far from
reality.

A great deal has changed since that time, as you are well aware. Many of you
in this audience have contributed to our expanding knowledge about AIDS or
are in some way associated with issues related to this deadly disease. As a result
you are familiar with its history. As of the beginning of April 1987, there were
among children under 13 years of age 471 reported cases that meet the Centers
for Disease Control (CDC) criteria for pediatric AIDS and 139 reported cases
among adolescents aged 13 to 19. The nearly 500 cases among young children
is double the number of cases reported only a year ago. Sixty percent of those
children have already died.

Unfortunately, we expect the number of infected children to continue to increase
dramatically. By 1991, the Public Health Service estimates that 3,000 children
will have suffered from the disease and virtually all will die. As frightening as
this may sound, the number is undoubtedly underestimated. We know that HIV
infection in children has manifestations that are legion; full-blown CDC-definition
AIDS is only part of the story. As many as 2,000 additional children are reported
to have symptoms of the infection, but do not fit the specific diagnostic criteria.

It has been found that congenitally acquired HIV infection may affect the infant’s
central nervous system (CNS) and thus may lead to alterations in growth and
development-—signs and symptoms not previously identified with AIDS.

With recognition of the wide clinical spectrum of HIV infection in children,
the CDC has developed a more detailed and exhaustive classification system for
the asymptomatic as well as the symptomatic child, the immunologically
compromised child, and the children with neurological disease, lung disease,
secondary cancer, cardiopathy, and nephropathy. We know this disease has many
presentations in children and, as our knowledge expands, our public health surveil-
lance will continue to reflect this knowledge.

The development of blood-screening procedures and methods of heat treating
blood-factor products virtually eliminated the risk of new pediatric AIDS cases
from blood and blood products. However, some children had earlier acquired

3
AIDS from contaminated blood. These children and their families also need our
attention. The burden suffered by these children, some of whom may also have
a severe chronic illness like hemophilia, is enormous.

About two-thirds of pediatric AIDS cases are the result of transmission from
infected mother to child. While there are other modes of transmission of infec-
tion to children and adolescents—sexual abuse, drug abuse, and sexual
intercourse —our major focus in pediatric AIDS must be on transmission from
the infected pregnant woman. Most of these mothers are intravenous drug abusers
or sex partners of drug abusers or of bisexual men. As the virus continues its
spread among the general population, however, a woman’s lack of direct involve-
ment with these high risk behaviors will be no guarantee against her infection
and transmission to her fetus.

Present information suggests that up to 65% of babies born to infected mothers
will contract the disease. The outlook for these children is almost certain death.

Currently, there are almost no programs that provide coordinated, community-
based care for pediatric HIV-infected patients. There is a lack of foster care place-
ment for HIV-infected infants and children. Pediatric units are overwhelmed by
the social and medical demands of both ill and well children with HIV infection.
There are not enough hospital personnel to provide and coordinate multi-
disciplinary inpatient, outpatient, community care, and just plain hugging and
playing with these children. Pediatric house staff in some institutions where the
prevalence of AIDS is high are concerned that their neonatal experience is skewed
because of the large numbers of neonates with AIDS.

Many of these children also suffer abandonment by the mother and society.
Because of the stigma of AIDS, there are fewer foster homes open to these chil-
dren. In fact there have been virtually impenetrable barriers between them and
a whole variety of social and public health services. Our infants and children
with this dread disease must be afforded a normal and dignified life. They must
be nurtured, helped to grow and develop, allowed to interact with peers, attend
school, and encouraged to enjoy and participate in all activities of childhood,
despite a shortened life span.

The AIDS epidemic is imposing severe social and economic burdens on many
communities. It will take combined resources from all levels of government and
the private sector to meet the increasing costs: of care for an expanding patient
population; of educational efforts to reduce high risk behaviors; of maintaining
an effective research effort for improved prevention, treatment, and cure; of the
social support to juveniles with AIDS and their families to secure the most normal
and dignified existence possible.

So far I have been focussing on the issues related to children with AIDS and
the heartfelt concern we have for these children. Although we have learned a
great deal about AIDS in a short time, our knowledge is nevertheless extremely
limited. Prudent judgment must continue to guide us. Under all circumstances
we must remain committed to providing humane and dignified care, and we must
be willing to bear the responsibilities and costs during the short, troubled lives
of these children.

Let us look at this profound tragedy from yet another perspective. Why is there
pediatric AIDS? The overwhelming majority of children with congenital AIDS
have this disease because of parental prenatal behaviors. While AIDS can afflict
children at all levels of society, it is occurring disproportionately in those who
have the least capacity and resources to cope. Over half of all babies born with
AIDS are black with one or both parents infected with AIDS. Another 25 percent

4
of all babies born with AIDS are Hispanic.

What we are seeing in reference to AIDS, therefore, is more tragic evidence
of high-risk pregnancies and births which are most likely to occur among black
women. . .who are poor. . .who are not ready for the world of work. . . who may
not even have a high school diploma. ..and who do not have ready access to
good prenatal and perinatal health care.

This population of young women produces a disproportionate number of low-
birth-weight babies. Life for these babies is a struggle from “day one”. . .and many
of them never make it to “day two.”

This is additional catastrophic news for the black community, already under
great economic and social stress. And it’s also more evidence of the apparent
inability of American society in general to make much headway in helping these
young women deal with their own sexuality and their own destinies.

Maternal infection with the HIV is preventable and so too is congenitally
acquired AIDS. Assembled here today is a group of national experts from the
sciences, the professional community, the government, and the community at-
large to address a public health problem of great importance to our nation and
to all people of the world. President Reagan has recently called AIDS “Public
Health Enemy No. |.” As the Surgeon General of the United States Public Health
Service, I am asking you to join with the President to bring all of our skill, exper-
tise, and resolve to focus attention on the broad range of health concerns related
to children suffering from AIDS.

Your task for the next several days will be to develop recommendations for
a national strategy for reducing the tremendous burden of this devastating condi-
tion, especially among our children. I ask that your recommendations give specific
attention to the development of an expanded knowledge base, the health resources
and services necessary to address the AIDS problem, and the social strategies
necessary to assure that our knowledge and resources are best applied in the service
of better health for our children.

The recommendations that will emerge from this Surgeon General’s Workshop
can change attitudes by utilizing calmness, confidence, and clarity in what we
say. We must be precise in the use of words lest we exacerbate fear which can
only lead to discrimination against children.

In dealing with the specific problems of pediatric AIDS, we need guidelines
for our communities to bring together local officials, health professionals,
educators, religious leaders, and parents to develop an interdisciplinary, moral,
and just approach for the battle against AIDS.

I wish you well and look forward to the fruits of your labors.

You really have the opportunity to make a major contribution to our under-
standing of pediatric AIDS, and also to the alleviation of some of the burden borne
by children with HIV infection and their families.
 

I fF Y O F PHILADELPHIA

WwW WILSON GCODE
MAYOR

April 6, 1987

CHILDREN WITH HIV INFECTION (AIDS)
AND THEIR FAMILIES WORKSHOP
Philadelphia, PA

TO ALL IN ATTENDANCE:

As Mayor of Philadelphia, I am privileged to extend
my best wishes on this most significant workshop, addressing
the issue of "Children with HIV Infection (AIDS) and Their
Pamilies."

This gathering is a special one, charged with the
important task of formulating recommendations to the Surgeon
General of the United States, C. Everett Koop, M.D., in
helping to set a national policy regarding this growing
problem. May all of you in attendance here today be re-
newed and encouraged in your efforts through the diverse
and informative Workshop sessions.

I express my admiration for the commitment and deter-
mination of all participants, and I offer my deepest hopes
that this workshop will be an unparalleled success in achiev-
ing its goals and objectives.

Sincerely,

Wb, fk

W. WILSON GOODE
Mayor

WWG :hs
EXCERPTS FROM PRESENTATIONS

THE GLOBAL EPIDEMIOLOGY OF THE
ACQUIRED IMMUNODEFICIENCY SYNDROME

Thomas C. Quinn, M.D.

Introduction

Since its initial recognition in 1981, the acquired immunodeficiency syndrome
(AIDS) has become a global pandemic. As of 1 March 1987, nearly 42,000 cases
had been reported from over 90 countries. Thirty-two thousand cases have been
reported in the United States, an additional 3,000 cases in the other countries
of the Americas, 4,500 cases in Europe, and 2,600 cases officially reported in
Africa—with several thousand suspected and many more unrecognized in that
continent alone. Australia and New Zealand had reported 404 cases for Oceania,
and 103 cases had been reported from 10 Asian countries. Because of under-
reporting, however, these numbers do not reflect accurately the true incidence
of AIDS worldwide. The World Health Organization estimates that there are over
100,000 cases of AIDS throughout the world, with a large majority of these cases
occurring in North America and Africa. An additional 300,000-500,000 cases
of AIDS-related conditions (ARC) and an estimated 5-10 million people world-
wide have already been infected with the virus that causes AIDS, the human
immunodeficiency virus (HIV).

  
  
 
   
       

       
   

Figure 1. 100,000 persons
300,000-500,000 with AIDS
persons with other
symptoms of HIV
infection aay,

Bat ie I ae
area

5-10 million
asymptomatic HIV
carriers

This latter group of infected people represents the human reservoir of this infec-
tion from which future cases of AIDS will emerge. In the United States, for
example, it is estimated that by 1991 over 270,000 cases of AIDS will have devel-
oped from the present pool of 1-2 million HIV-infected individuals. In that year,
over 54,000 deaths will occur from AIDS, and AIDS will be ranked as one of
the leading causes of premature death in our society. For other areas, particu-
larly Central Africa, where already 10%-15% of the general population has been
infected by the AIDS virus, these numbers will be even greater. With conserva-
tive estimates of 20%-30% of HIV-infected people developing AIDS within a

7
five year period, and with an 80% mortality rate two years from time of diag-
nosis of AIDS, AIDS has clearly established itself as one of the most serious
epidemics of the century.

AIDS is characterized by the unusual appearance of life-threatening opportunistic
infections or malignancies occurring in an individual who has a severe depres-
sion of the cell-mediated immune system. Under this clinical case definition,
31,834 patients (including 31,381 adults and 453 children) have been reported
as AIDS cases to the CDC as of 2 March 1987. Of these patients, 18,835 (57%
of adults and 61% of children) are known to have died, including over 80% of
those patients diagnosed before January 1985. Since the initial reports of AIDS
in early 1981, the number of cases reported for each 6-month period continues
to increase. However, the increases are not exponential, as evidenced by the length-
ening period of time required to double the number of cases.

Cases have now been reported from all 50 States, the District of Columbia,
and the 4 U.S. territories. Fifty-three percent of all the cases have been reported
from New York and California, and the incidence rate of AIDS for New York
City and San Francisco is approximately 100 cases/100,000 population.

Adult Patients

Ninety-seven percent of all adult AIDS patients can be placed in a group that
suggests the possible means of disease acquisition. Homosexual or bisexual men
not known to have used intravenous drugs represent 65% of all reported cases,
or 70% of the male cases. Heterosexual IV drug users comprise 17% of all cases,
including 15% of the male cases and 51% of the female cases. Homosexual or
bisexual men who have used IV drugs comprise 8% of all cases. Persons with
hemophilia or coagulation disorders who have received Factor 8 or Factor 9
concentrates represent 1% of all cases. Heterosexual partners of persons with
AIDS or at risk for AIDS represent 4% of all cases, including 2% of the males
and 27% of the females. The proportion of female AIDS cases in this risk group
increased significantly between 1982 and 1986 from 12% to 27%, a trend which
may prove to be a good marker for following patterns in heterosexual transmis-
sion. This last category of heterosexual partners also includes those who, without
other identifiable risk, were born in countries in which heterosexual transmis-
sion is believed to play a major role, such as in Haiti and Africa. Recipients of
transfused blood or blood components comprise 2% of all cases, which represents
1% of male cases and 10% of the female. For 3% of AIDS patients, the possible
means of disease acquisition is undetermined, in these cases primarily due to lack
of epidemiologic investigations before death.

 

Table 1. Distribution of Etiologic Risk Factors in AIDS Patients in the U.S.A.

Male (93%) Female (7%) Total

Homosexual or bisexual men (Non-IVDU)* 10% - 65%
Homosexual or bisexual men (FVDU) 8% - 8%
Heterosexual IVDU 15% 51% 17%
Heterosexual partners of persons with AIDS 2% 27% 4%
Coagulation disorders 1% >1% 1%
Other transfused patients 1% 10% 2%
Undetermined risk factor 3% 11% 3%
100% 100% 100%

 

*(IVDU = Intravenous Drug User) (Total 31,381 patients at March 2, 1987)

8
Pediatric Patients

The percentages displayed in Table 2 have remained fairly constant in the weekly
CDC reports. An additional undetermined number of children with evidence of
HIV-infection are not included in these numbers because they do not fit the CDC
definition for AIDS. These children are defined as having AIDS-related complex
(ARC), not a reportable syndrome at this time. Many, if not all, will progress
to AIDS.

 

Table 2. Demographic and Clinical Distribution of Pediatric AIDS Patients < 13 years)

AGE: ETIOLOGIC RISK FACTORS:
(a) < 5 years (88%) (a) Parent with AIDS or in high-risk category (80%)
(b) > 5 years (12%) (b) Blood transfusion (12%)
RACE: (c) Concentrate for coagulation disorders (5%)
(a) Black (57%) (d) Not known (3%)
(b) Hispanic (22%) CLINICAL DIAGNOSIS:
(c) White (20%) (a) Pneumocystis carinii pneumonia (52%)
SEX: (b) Other opportunistic infection (47%)
(a) Male (55%) (c) Kaposi’s sarcoma (1%)

(b) Female (45%)
(Total 453 patients at 2 March 1987)

 

Pediatric patients have been reported from 29 States, the District of Columbia,
and Puerto Rico, with 72% of the pediatric patients reported in Florida, New
Jersey, and New York. Since the majority of AIDS cases in children are the results
of perinatal transmission from the mother, trends in female AIDS cases may also
predict future trends for AIDS in children.

Other Countries

The epidemiology of AIDS in other countries of the Americas, such as Canada
and Brazil, and in Europe is quite similar to that described for the United States.
The male-to-female ratio is 13:1, and there is a predominance of cases occurring
among homosexual or bisexual men and intravenous drug users. However, in
tropical countries such as in Africa and Haiti, the male-to-female ratio is 1:1 and
the majority of cases are identified among heterosexually active individuals who
deny the above risk factors. Currently, an accurate assessment of the exact number
of cases and risk factors for transmission among those cases is not entirely feasible,
due to these developing countries’ lack of resources to support an accurate surveil-
lance system. Serologic surveys for HIV infection and preliminary AIDS surveil-
lance studies using modified case definition, however, have provided useful
information regarding the spread of HIV infection and AIDS in these areas.

In areas where international scientific teams have been monitoring AIDS, it
is estimated that the annual incidence of AIDS is approximately 200 cases/100,000
population, a rate twice that observed presently in New York City or San Fran-
cisco. The male-to-female ratio of AIDS cases in Central Africa is approximately
1:1, and the sex and age-specific distribution of AIDS cases reflects patterns seen
with other sexually transmitted diseases in which the incidence and morbidity
rates are higher among younger women and older men. Serologic studies have
indicated prevalence rates of HIV antibody ranging from 5%-88% for blood
donors, 27%-88% among female prostitutes, and 2%-10% among pregnant
women of Central Africa. Longitudinal data on HIV seroprevalence have shown
a rapid rise in HIV antibodies among prostitutes in Kenya from 4% in 1980 to
59% in 1986. These data demonstrate the rapid spread of HIV infection in a high

9
risk heterosexually active group in Africa. Exposure to infected blood transfu-
sions and blood-contaminated needles used for medicinal purposes further amplify
the transmission of HIV among the general population of these tropical areas.
Consequently, the entire Central African population has become at risk, and some
natural history studies have already documented there a 1% annual seroconversion
rate in a general heterosexual population.

As a result of heterosexual transmission, African women of child-bearing age
are exposed to HIV. As in U.S. studies, maternal HIV infection appears to be
strongly associated with seropositivity among infants in Africa. In one city of
Central Africa, approximately 8% of all infants are born to seropositive mothers.
While it is unclear what percent of these children will acquire HIV infection perina-
tally, it is evident that a substantial number of newborn children are presently
being infected with HIV. Children in developing countries are also at risk for
acquiring HIV infection from unscreened blood transfusions for the anemia
associated with malaria, malnutrition, and other endemic diseases, as well as from
exposure to blood-contaminated needles and syringes used for medicinal purposes.
Thus, it can be anticipated from these data that HIV infection will have a dramatic
effect on the general health of these children and potentially on the safety and
efficacy of childhood vaccinations.

New Viruses

This problem in Africa is now being exacerbated by the appearance of addi-
tional human retroviruses, referred to as HTLV-IV or LAV-2, or HIV-2, some
of which may cause symptomatic disease, including AIDS. Infection with these
retroviruses is rapidly spreading throughout West Africa, primarily by heterosexual
transmission, blood transfusions, exposure to blood contaminated needles and
syringes, and perinatally from mother to infant. Diagnostic assays for HIV-2 are
not entirely reliable for detection of infection with these other human retroviruses,
and new methods need to be developed rapidly to help control the spread of these
retroviruses. Additional studies on the relationship of these human retroviruses
to HIV, including genomic and protein comparisons, as well as on the patho-
genicity and natural history studies, will help facilitate the development of safe
and effective vaccines against these human retroviruses.

Summary

With an estimated 5-10 million people already infected with HIV, and with
projections of 1-2 million cases of AIDS occurring worldwide over the next several
years, it is evident that AIDS has clearly become established as a global pandemic,
presenting an unprecedented health problem for our society. Unless control efforts
are successful, HIV infection will continue to spread rapidly by sexual, parenteral,
and perinatal modes of transmission. Until a safe and effective vaccine is avail-
able, prevention of HIV transmission must rely primarily on educational programs,
modification of sexual practices, screening of blood transfusions, and intensive
counseling of seropositive individuals. Faced with one of the greatest epidemics
of our lifetime, we must make prevention and control of HIV infection an inter-
national public health priority, requiring the full commitment of the necessary
political, financial, and professional resources of all countries.

10
THE HUMAN IMMUNODEFICIENCY VIRUS

Wade Parks, M.D., Ph.D.

The virus etiologically associated with AIDS is a member of the Family
Retroviridae. A defining characteristic of this family of viruses is that they have
a diploid linear single-stranded RNA genome that is surrounded by a protein
capsid. The capsid is surrounded by a lipoprotein envelope. This envelope or
coat is covered with viral glycoproteins that are involved in viral entry into suscep-
tible cells and is a major target of the host immune system. A unique marker
of the Family Retroviridae is the reverse transcriptase which is a part of the virion
and which catabolizes the synthesis of DNA from RNA and is thus an RNA-
dependent DNA polymerase. The AIDS virus is a member of one of the sub-
families of Retroviridae.

Free Free

Virion Virton
‘O; Aitachment te}
gy ee Budding ae
‘ } ( / \ ]

~
Translation Genomic

 

 
 
 
   

Reverse
Transcription

  
 

Free
Circular
ONA

     

 

 

 

 

 

 

 

 

 

The life cycle of a retrovirus

Figure 1.

The subfamily Lentivirinae that contains the AIDS retrovirus includes a number
of unglulate viruses associated with chronic, persistent infections in their natural
hosts. These include Equine Infectious Anemia (EIA) or “swamp fever” described
first in 1904, Visna—the prototypic lentivirus which causes a neurologic disease
of sheep, and Caprine Arthritis and Encephalitis Virus (CAEV). The morphology
of lentivirus virions is relatively unique with an elongated, bar-shaped nucleoid.
Lentiviruses have a slightly larger genome than most retroviruses, and a larger
and more highly variable virion external glycoprotein than other retroviruses.
Thus far, the reverse transcriptase differs only slightly, preferring a different
divalent cation—magnesium—over manganese.

11
The etiologic agent of AIDS was originally termed the Lymphadenopathy-
Associated Virus or LAV by Luc Montagnier and his co-workers at the Institut
Pasteur in Paris. When Robert Gallo and his colleagues at the National Cancer
Institute repeatedly isolated virus from AIDS patients, they referred to their isolates
as Human T-Lymphotropic Virus type Il, or HTLV-II. Gallo and his group
had already described an HTLV-I and HTLV-II, human-infecting members of
the Family Retroviridae, subfamily oncovirinae. Hence, the etiologic agent of
AIDS was called HTLV-II in this country and LAV in Europe and frequently
abbreviated HTLV-III/LAV. More recently, a group of virologists have recom-
mended the term, Human Immunodeficiency Virus (HIV), for the AIDS virus.

The retrovirus of AIDS has a structure that is similar to other retroviruses.
This means that the linearized form can be depicted as bound on either end by
two non-coding regions known as long terminal repeats (LTRs). Moving 5’ to
3', the gene order is gag, pol, and env between the LTRs. The gag gene encodes
for structural proteins of the virus, including the p24 molecule, which is the most
abundant polypeptide of the virion and which is very important as a diagnostic
marker in infected patients. The pol gene encodes for the reverse transcriptase,
a remarkable polyfunctional molecule which subserves proteolytic, catalytic, and
integration activities within newly infected cells. The env gene encodes for the
virion surface proteins, which are glycosylated, hence glycoproteins. The trans-
membrane protein is known as p41E and is the major component of newer recom-
binant diagnostic seroassays for detecting infection. The external glycoprotein
is known as gp120. The gp120 contains the region that forms the attachment to
the viral target, the CD4 molecule that characterizes certain T-lymphocytes. This
high affinity ligand interaction is the mechanism by which the virus can infect
cells. Antibodies to the gp120 can neutralize viral infectivity. The gp120 has
multiple regions that are highly variable in genetic sequence; these regions differ
from one virus to another. Thus, the virus varies markedly, enabling the virus
to avoid elimination by the host’s immune system.

Finally, the AIDS retrovirus has some additional genetic features that demon-
strate its amazing versatility. Within the virus there are a number of open reading
frames that have the capacity to encode for proteins. Two of these have been
described: tat and art. Both are products of spliced mRNAs and appear to subserve
important biological roles for viral replication. The tat gene especially codes for
a protein that binds to a very specific region of the 3-LTR and then enhances
transcription. Since the protein can act in trans, it is called the trans activator
(tat). The tat gene product serves to turbocharge the replication of the AIDS
retroviruses. Hence, in the short time that an infected lymphocyte may undergo
cell division in response to a given antigenic stimulus, tat and its related proteins
allow maximal production of the retrovirus and thereby increase the probability
for successful virus infection of other lymphocytes.

In general, the retrovirus of AIDS is a highly adapted pathogen. Its genetic
functions subserve two essential prerequisites for any virus’s survival, replica-
tion and avoiding immune elimination. A full knowledge of the molecular
mechanisms of viral replication and their relevance may be central to the control
of the AIDS epidemic.

12
THE IMMUNOLOGY OF PEDIATRIC AIDS

Arthur J. Ammann, M.D.

The pathogenesis of AIDS, felt to be a result of HIV infection, is best studied
in infants and children, since they represent a more pristine host. Undoubtedly,
HIV infection and its resultant clinical manifestations are a consequence of infection
with this retrovirus as well as the interaction between HIV and other preexisting
or subsequent infectious agents. Studies of infants suggest that HTV infection alone
may result in impairment of the immune system and secondary susceptibility to
opportunistic infection. Even in the case of isolated HIV infection, however, the
clinical manifestations and severity of the disease may vary, implying that the
time at which infection occurs (as early as 20 weeks gestation), the amount of
viral inoculum, and preexisting immunodeficiency are important variables.

Experimental evidence suggests that the monocyte/macrophage may be the initial
cell infected with HIV and may subsequently be a major source of continued virus
replication and infection. It is important to emphasize that certain organs have
significant numbers of monocytes and macrophages that are CD4 receptor-positive
(the CD4 receptor is required for HIV infection of cells). This may provide an
explanation for the occurrence of the isolated brain and lung involvement some-
times observed in infants with HIV infection. In vitro infection of monocytes with
HIV may result in giant cell formation, with a histologic appearance similar to
that of the giant cells found in tissue sections obtained from the lung and brain
of HIV-infected patients.

The interaction of HIV and other viruses may result in clinical features unique
to either adult AIDS or pediatric AIDS. For example, Kaposi’s sarcoma—a
frequent malignancy in AIDS—has not been convincingly demonstrated in pedi-
atric AIDS. On the other hand, chronic parotid swelling and pulmonary lymphoid
interstitial pneumonitis (LIP) are frequently found in pediatric AIDS but rarely
observed in adult AIDS.

The pathogenesis of LIP was linked to infection with Epstein-Barr virus (EBV)
in several studies which used EBV DNA probes to detect the presence of virus
in lung tissue. The response to EBV infection in patients with AIDS is abnormal.
In EBV-infected infants with AIDS followed prospectively, virus was cultured
for several weeks prior to appearance of antibody to EBV antigen. There was
an absence of an IgM anti-VCA response and failure to develop antibody to
Epstein-Barr Nuclear Antigen (EBNA). IgG antibody to Anti-Viral Capsid Antigen
(VCA) and antibody to Early Antigen (EA) remained high in most patients,
suggesting persistent chronic EBV infection. This is in contrast to normal
individuals where infection results in an initial increase in antibody to VCA,
followed by a decline to low levels which persist for life.

Patients with pediatric AIDS and EBV infection also have prolonged
virocytemia, easily recoverable EBV, and increased numbers of EBV-infected
cells. It is possible that the existence of HTV infection in the lung, followed by
EBV infection, results in a lymphoid proliferative response manifested as LIP.
EBV-infected B cells are more susceptible to HIV infection than uninfected B
cells and may be stimulated by HIV antigens to excessive proliferation. A
suggested interaction between HIV and EBV was based on observations in EBV-

13
infected adults who subsequently became infected with HIV and developed addi-
tional immunologic abnormalities. The more common sequence of infection in
pediatric AIDS, HIV followed by EBV infection, may result in a lympho-
proliferative disorder. Adults have a reverse sequence more commonly, and they
rarely develop LIP.

The presence of LIP may modify the susceptibility of infants to opportunistic
infection. Two studies note that patients with LIP had fewer opportunistic
pulmonary infections and that patients with Pneumocystis carinii pneumonia (PCP)
do not have evidence of pulmonary hyperplasia.

HIV infection of immunocompetent cells may result in immunodeficiency by
several mechanisms. Following infection, syncytia formation and fusion of cells
occur with subsequent death in vitro. A similar mechanism in vivo could result
in T-cell depletion. Cytotoxic T-cells may also destroy infected cells in vivo
resulting in reduced numbers of T4 cells and the characteristic reversed T4/T8
ratios seen in most patients. However, early immunologic abnormalities occur
prior to depletion of immunocompetent cells, suggesting that HIV infection may
directly interfere with immune function. For example, HIV infection of T-cells
in vitro results in decreased IL-2 and CD4 receptor mRNA and IL-2 and CD4
receptor expression. It is also known that Peripheral Blood Mononuclear Cells
(PBMC) from patients with AIDS and preAIDS have decreased cytokine produc-
tion in vitro. Many of these cytokines are essential for immune interaction,
antiviral, and antitumor effects. Deficiencies of interferon-a (IFN-a), interferon-y
(IFN-y), tumor necrosis factor-a (TNF-a), tumor necrosis factor B (TNF-B),
interleukin-2 (IL-2), and interleukin-1 (IL-1) have been described. One or more
cytokine deficiencies may result in secondary defects, such as abnormal monocyte/
macrophage function, decreased natural killer-cell activity, decreased antibody
formation, and decreased T-cell immunity.

Abnormalities of macrophage function may play a more critical role in the patho-
genesis of HIV-induced immunodeficiency than previously appreciated. The
macrophage may act both as a reservoir of HIV infection and, as a result of its
central role in the T- and B-cell immunity, may play a primary role in early
immunodeficiency.

Immunodeficiency following HIV infection may also result from the
immunosuppressive effects of HIV envelope glycoprotein or other immuno-
suppressive regions of virus proteins. Following HIV infection, envelope
glycoproteins are secreted to the surface of cells. Several regions of the envelope
glycoprotein are capable of suppressing the immune response in vitro.
Glycoprotein 120 (gp120) is capable of binding to the CD4a region of the CD4
receptor and interferes with immune function in vitro as measured by mitogenic
and antigenic stimulation.

Prospective studies of patients with AIDS suggest that B-cell abnormalities may
precede other laboratory features of immunodeficiency. Patients usually have
polyclonal hypergammaglobulinemia. This may result from chronic HIV antigen
stimulation or loss of suppressor T-cell regulation. In contrast, antibody levels
to HIV antigens are not markedly elevated as is usually observed in other chronic
viral infections. Further, specific IgM antibody to HIV is difficult to demonstrate
in either acute or chronic infection. As the syndrome progresses, patients lose
their ability to respond to other antigens following immunization.

14
 

Table 1. B-Cell Abnormalities in AIDS

@ Polyclonal hypergammaglobulinemia
@ Failure to produce antibody following immunization
Mi Increased spontaneous IgG secretion, due to:
1) antigenic stimulation by HIV
2) increased numbers of EBV infected cells
3) HIV-induced T-cell dependent B-cell activation
@ Decreased B-cell response to antigens
W Decreased B-cell response to T-cell independent mitogens

 

T-cell abnormalities are numerous and profound. Early abnormalities consist
of inability of PBMC to respond to antigens in vitro and of cytotoxic T-cells to
kill target cells. In vivo, this correlates with absence of reaction to delayed hyper-
sensitivity skin tests. As the syndrome progresses, PBMC from patients lose their
ability to respond to mitogens and alloantigens and are unable to produce normal
amounts of essential cytokines (IFN-a, IFN-y, TNF-a, TNF-B, IL-1, IL-2). The
broad-based T-cell deficiencies are most likely a result of both intrinsic abnor-
malities and severe T-cell depletion.

 

Table 2. T-Cell Abnormalities in AIDS

Number Function
@ Lymphopenia @ Absent delayed hypersensitivity skin tests
W@ Decreased T helper cells (decreased H/S @ Diminished PBMC response to antigens
ratio) @ Diminished PBMC response to mitigens
Decreased T suppressor cells (PWM, Con A, PHA)
@ Increased Dr and OKT10 expression on @ Decreased cytokine production
CD8 cells IL-1, IL-2
IFN-a, IFN-y
TNF-a, TNF-B

@ Decreased Thymic hormones (thymulin)

 

A number of monocyte defects have been reported in AIDS. Monocytes fail
to mature at a normal rate, do not have normal chemotaxis and adherence, and,
as determined by use of certain in vitro assays, are unable to kill some micro-
organisms. An unanswered critical question is whether antigen processing or
antigen presentation of HIV-infected macrophages is abnormal.

The major abnormality of the complement pathway which has been described
in AIDS is that of increased immune complex formation. This is probably a result
of both non-specific polyclonal hypergammaglobulinemia and chronic antigenemia
as a consequence of chronic infection with a number of microbial agents. Some
of the severe consequences of chronic immune complex formation, such as renal
failure, are rarely observed in patients with AIDS. However thrombocytopenia,
which is more commonly found, may result from removal of immune complex
coated platelets from the circulation.

15
 

Table 3. Complement Abnormalities in AIDS

B® Increased circulating immune complexes
™@ Increased HIV specific immune complexes
@ Immune complex deposition (renal disease, thrombocytopenia)

 

In order to establish a diagnosis of HIV infection, either antibody to HIV or
the presence of HIV must be demonstrated. A number of tests for antibody are
commercially available. Most of these are enzyme-linked immunosorbent assays
(ELISA) and utilize HIV antigens coated on to plastic surfaces to detect IgG anti-
body in the test serum. The assays are designed to be highly sensitive and there-
fore readily detect antibody positives, but as a consequence also have a high rate
of false positives.

 

Table 4. Enzyme Linked immunosorbent Assay (ELISA)

@ Method
1) Disrupted virus placed in plastic wells or on plastic beads
2) Incubated with test serum
3) Antibody to antigen detected by enzymatic reaction.
@ Characteristics
1) Sensitive - best for screening
2) High number of false positives
(<50% are confirmed positive by Western blot)
3) A positive must be confirmed by Western blot

 

It is necessary to confirm each positive by first repeating the ELISA and then,
if again positive, confirming the presence of antibody to specific HIV antigens
by a Western blot. Other antibody assays include indirect immunofluorescence
and radioimmunoprecipitate assays and are primarily for investigational purposes.

A major difficulty in the diagnosis of HIV infection in newborns and infants
is the inability to differentiate between passively transferred maternal IgG anti-
body to HIV and actively produced antibody from the infant. Unfortunately IgM
antibody to HIV has been detected only inconsistently. There are several other
methods of establishing HIV infection in the infant. Serial antibody testing by
Western blot may demonstrate the emergence of new antibodies to HIV antigen.
Culture of PBMC for virus or the use of DNA probes may demonstrate presence
of HIV, but the methods are currently less sensitive than antibody assays. Newly
developed assays for the detection of HIV antigen in serum may provide an alter-
native means of testing.

A diagnosis in pediatric AIDS can be confirmed using a few well established
assays of immunologic function coupled with assays for virus infection or demon-
stration of viral antigen. The confirmation of HIV infection is essential to provide
appropriate care for infected infants and children.

16
TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS
INFECTION IN THE UNITED STATES

Martha F. Rogers, M.D.

The human immunodeficiency virus (HIV) is transmitted by three routes:
1) from mothers to infants during the perinatal period, 2) through parenteral
exposure to infected body fluids, primarily blood, and 3) through sexual contact.
Although other modes of transmission have been proposed, including transmis-
sion through casual contact, through insect bites, through exposure to contami-
nated needles used for tatooing, ear piercing, or acupuncture, and through receipt
of hepatitis-B vaccine or immune globulin, there is little or no evidence supporting
such occurrence.

Perinatal Transmission

Perinatal transmission accounts nationwide for about three-quarters of cases
of HIV infection in prepubertal children. The epidemiologic characteristics of
these children closely parallel those of heterosexual adults with AIDS, particu-
larly women. Over half (65%) of reported cases of AIDS in women, 69% of
heterosexual men with AIDs, and 73% of the perinatally acquired AIDS cases
in children were related to IV drug abuse or sexual contact with IV drug abusers.
The geographic areas most affected by heterosexual and perinatal transmission
have been the New York City metropolitan area, northern New Jersey, and
southern Florida. The majority of heterosexual men (74%), women (72%), and
children with perinatally acquired infection (88%) have been black or Hispanic.
Most are inner-city dwellers of low socioeconomic status.

Evidence suggests that perinatal transmission can occur by three modes:
1) transplacental passage of the virus in utero, 2) exposure to infected maternal
blood and vaginal fluids during the labor and delivery of the infant, and 3) post
partum ingestion of breast milk containing the virus. The proportion of perinatally
acquired cases attributable to each of these modes is unknown.

Preliminary data from prospective studies of infected women and their infants
indicate that the frequency of transmission from mothers to their infants may be
as high as 50%. Both symptomatic and asymptomatic women can transmit HIV
to their infants. The risk factors associated with transmission, however, have not
been defined. Mothers can transmit HIV in more than one pregnancy. Each
infected infant is at risk of developing AIDS.

 

Table 1. Possible Risk Factors for Transmission of HIV from Mothers to Their Infants

Virai factors—viremia, latent vs. active infection, % cells infected
Substance abuse or other environmental/behavioral factors

Other infections present

Level of immune suppression

Continued exposure to HIV

Host factors

 

17
These prospective studies also indicate that maternal HIV infection is probably
not associated with adverse prenatal or neonatal infant outcomes, nor with an
increase in obstetrical complications. Two studies have reported an increased
frequency of spontaneous abortions among seropositive women, but three other
studies have not observed this trend. To date none of the women in the CDC
Classification-3 or less developed AIDS during the pregnancy. In one study,
however, a trend towards an increased incidence of hospitalizations for infections
in seropositive versus seronegative pregnant women was observed. In addition,
a greater proportion of seropositive pregnant women developed complications
during an average of 6 months’ follow-up postpartum, compared with seropositive
women who did not become pregnant and who were followed an average of
12 months.

Parenteral Transmission

Transmission through parenteral exposure to infective body fluids has occurred
primarily in 2 populations: 1) in persons sharing contaminated needles used to
inject illicit drugs, and 2) from donors to recipients of blood or blood products.
Transmission through accidental injuries with contaminated needles or other cutting
objects in the health care setting has been extremely rare, occurring in less than
1% of such injuries.

About one-fifth of reported AIDS cases are attributable to transmission through
use of contaminated needles for injecting illicit drugs. Seventy-four percent of
these patients come from New York and New Jersey. Seroprevalence studies of
IV drug abusers have shown infection rates of up to 70% in these areas, 42%
in Boston, 11% in Chicago, and 10% in San Francisco. Several studies have shown
that in IV drug abusers, seroprevalence is highest in those who are black or
Hispanic.

Transmission through receipt of infected blood or blood products accounts for
3% of adult and 17% of the pediatric AIDS patients nationwide. Cases are scattered
throughout the United States with California and New York having the greatest
number of cases. Most of the children with transfusion-acquired AIDS were trans-
fused in the neonatal period or had coagulation disorders.

No cases of transfusion-acquired AIDS have been reported in children trans-
fused after initiation of donor screening for HIV antibody in March-April 1985.
Although transmission through transfusion of seronegative blood can occur when
the donor is in the early stages of HIV infection and is viremic but not yet producing
antibody, this has been rare.

In one study of the recipients of blood collected prior to HIV screening from
donors who later developed AIDS, the risk of HIV infection following receipt
of blood from an infected donor approached 100%. In instances of split donations,
in which one recipient became infected, so did the other. Once a seropositive
donor transmitted the virus to a recipient, all subsequent recipients of blood from
that donor also became infected.

Although donor screening procedures and heat treatment of coagulation products
have markedly reduced the transmission of HIV through these routes, cases of
AIDS in persons who received these products before these interventions will
continue to occur. The incubation period for AIDS in adults with transfusion-
acquired infection averages 3 years and has been as long as 7 years. The incubation
is shorter for children, averaging 2 years and ranging up to 6 years.

18
Sexual Transmission

Sexual contact is the most common mode of HIV transmission in adults, and
accounts for over three-quarters of reported cases. Sexual contact between
homosexual or bisexual men has accounted for 95% of sexually acquired HIV
infection, but heterosexual transmission is increasing, particularly in minority
populations. In contrast to gay male cases, about three-quarters of women with
AIDS and of heterosexual men with AIDS are black or Hispanic.

The frequency of transmission between heterosexual sex partners is around
10%-15% in the partners of hemophiliac men and transfusion recipients, about
40% in the non-drug-abusing partners of IV drug abusers, and about 58% in a
study of partners of primarily IV drug abusers and Haitian immigrants. Some
persons have acquired infection after only a few at-risk sexual encounters, while
others did not acquire infection despite repeated contact over several years.
Medical conditions (such as cervicitis or vaginitis), menstruation, and sexual prac-
tices (anal intercourse) that involve greater exposure to blood and friable tissues
increase the likelihood of transmission. Transmission has occurred, however, in
persons engaging in vaginal intercourse exclusively and without any of the above
conditions.

Casual Contact

Transmission through close but nonsexual contact (so called “casual”) has been
extremely rare. Only three possible cases have been reported. Two of these cases
involved nursing care of bedridden patients associated with extensive and repeated
contact with blood and body fluids of the infected patient. The other case involved
apparent transmission between two siblings, but the nature of the contact was
not well characterized. Nine other independent studies of over 400 family members
of HIV-infected patients have not found evidence of household transmission. In
addition, none of the family members of the over 30,000 AIDS cases reported
to the Centers for Disease Control (CDC) has developed AIDS as a result of house-
hold contact.

Intervention methods designed to prevent further spread of HIV infection must
consider the epidemiology of the infection including the modes of transmission,
the characteristics of the currently affected populations, and the potential for spread
within these populations and to other groups.

19
APPROACHES TO PREVENTION OF HIV INFECTION

Walter R. Dowdle, Ph.D.

The five basic mechanisms for prevention of infectious diseases include
1) immunoprophylaxis (vaccine), 2) chemoprophylaxis/therapy (drugs),
3) sanitation (environment), 4) lifestyle modification (behavior), and 5) vector
control. Of these five mechanisms, the first four are applicable to prevention of
HIV infection. There is no evidence to suggest that the AIDS virus is transmitted
through insect or other vectors.

The first two of the four mechanisms, vaccines and prophylactic/therapeutic
drugs, are under development. Ideally, both will be incorporated into future strate-
gies. Much progress has been made toward understanding the basic properties
of potential retrovirus vaccines, but 5 to 10 years or more may be required before
a vaccine can be realistically considered as a public health tool. How a vaccine
will be utilized in prevention strategy will depend upon its availability, cost,
efficacy, and safety. Greater promise has been shown for antiviral drugs, partic-
ularly as we learn more about the pharmacology and clinical efficacy of certain
classes of drugs.

For the present, however, our strategy must rely on the two remaining
mechanisms, modifying the environment and modifying personal behavior.

Modifying the environment is of limited benefit, but some changes have already
been accomplished. Tests for screening the blood of donors for HIV antibody
have been used regularly for nearly two years. This screening has vastly reduced
the risk of transfusion-associated infections. Donor screening and treatment of
factor VIII has virtually eliminated the risk of AIDS for persons with hemophilia.
The environment does not pose a major risk for health care workers. Needlestick
injury would appear to be the greatest concern, but recommendations for caution
by health care workers have been widely disseminated. Our main task has been
to reassure the public that the general environment does not present a threat. The
virus is not transmitted through casual social contact or food and water.

The remaining and most important mechanism for prevention consists of
modifying behavior. This is a difficult and often controversial task that in the
past has not been considered effective for other sexually transmitted diseases
(STDs). Nevertheless, we must make a concerted effort to develop effective educa-
tional programs regarding HIV infection. Specific mechanisms for modifying
behavior include modification of sexual practices of infected persons, routinely
offering testing and counseling to persons at high risk, treating IV drug abusers
to preclude transmission of the virus through the use of contaminated needles,
and information and education programs. There is considerable evidence that risk
reduction already has occurred in the gay community.

Effective information/education programs include a whole spectrum of activi-
ties, ranging from TV spots to individual counseling sessions. An effective
program requires multiple channels of information tailored to specific audiences
and delivered through the auspices of a wide range of private and public organi-
zations and institutions. The Public Health Service Information/Education Program
is directed to the general public, to school- and college-aged young persons, to
other persons at increased risk, and to health workers. The program is budgeted

20
at over 79 million dollars, with 102 million proposed for next year. The general
public can be informed and educated through hotlines, coalitions, ad campaigns,
and clearinghouses. That, of course, forms the foundation and background on
which more specific programs aimed at high-risk groups can be developed. Each
of the nation’s school systems will decide how best to implement education in
AIDS prevention at appropriate ages. There is less argument here than may appear
on the surface. Our interest is in assisting local school groups in developing their
own curricula. We are trying to facilitate that activity, but by no means is the
Federal government attempting to tell anyone what to teach. The individual school
boards will make their own decisions. We do feel that there is great demand and
eagerness in the schools to move on the education issue.

Efforts at educating health workers can be productive, because they are a major
channel of information to infected patients and in carrying preventive informa-
tion to others.

When we speak of educating those at increased risk for pediatric AIDS, the
preferable strategy is to prevent infection in women of child-bearing age. This
is a very difficult area. Those at increased risk are the female sex partners of
men at high risk, intravenous drug users, prostitutes and clients. These are diffi-
cult to reach. The second line of defense is to provide counseling to those already
infected to help them enter into a program of comprehensive health care and
follow-up, including avoidance of pregnancy. After that, our options grow less
and less clear.

In some geographic areas and for some populations, these information/educa-
tion activities are beginning. To ensure maximum effectiveness, these programs
must be constantly evaluated and modified if necessary. Increased knowledge and
general awareness of prevention information is important, but our ultimate criterion
of success must be a change in personal behavior that results in decreased trans-
mission of infection.

21
NATURAL HISTORY OF HIV INFECTION IN CHILDREN

Gwendolyn B. Scott, M.D.

One hundred thirty-four cases of perinatal Human Immunodeficiency Virus
(HIV) infection were identified in South Florida between January 1981 and
December 1986. Each year since 1981, we've seen an increasing number of cases.
In 1986 we identified one-third of our total case load, and so far in 1987 we are
seeing at least one new case per week. These infants were born to 109 infected
women. Drug abuse accounted for 22% of the disease in the mothers in compar-
ison to 60% reported nationally. Fifty-one of these children meet the CDC surveil-
lance criteria for AIDS; 81 others have clinical symptomatology and are diagnosed
as ARC. Two, who are now 7 years old, are asymptomatic.

Ninety-two percent of these children were black. The majority of children
presented with clinical disease in the first two years of life (74%). There are,
however, a number of children who present between the ages of 2 and 6 with
the first manifestations of disease. The overall mortality in these children is 35 %,
but among those who meet the criteria for AIDS, the mortality is 73.5%.

Pneumocystis carinii pneumonitis (PCP) and Candida esophagitis are the most
common opportunistic infections. Failure to thrive is the presenting complaint.
Lymphadenopathy, hepatosplenomegaly, and persistent oral thrush are some of
the more common findings. We have seen disseminated cytomegalic virus infec-
tion frequently, five cases of cryptosporidiosis, and one case of Mycobacterium
avium-intracellulare. Tumors occur, but are rare in children. We have a few cases
of Kaposi’s sarcoma, one of lymphoma of the liver, and one of Burkitt’s lymphoma
of the lung. Opportunistic infections presenting in the first year of life are
associated with a higher mortality.

In an effort to better describe the clinical outcome of infection in pediatric cases,
a syndrome approach has been applied.

 

Table 1. Syndromes Associated with Pediatric HIV Infection

Wasting Syndrome

Lymphoid Interstitial Pneumonitis
Recurrent Bacterial Infection
Encephalopathy
Lymphadenopathy Syndrome
Cardiomyopathy

Hepatitis

Renal Disease

 

More than one of these syndromes may occur in the same patient separately or
simultaneously. There appears to be a relationship between the immune response
and the development of these syndromes. For example, patients with early onset
pneumocystis pneumonitis or encephalopathy tend to have decreased evidence
of immune response and have a higher mortality. In comparison, patients with
LIP, lymphadenopathy syndrome, cardiomyopathy, recurrent bacterial infections,
or renal disease generally have a lymphoproliferative response with hyper-

22
gammaglobulinemia, lymphadenopathy, and hepatosplenomegaly. Children with
PCP have an earlier age of onset and a higher mortality rate than those with LIP.

 

Table 2. LIP and Early Onset PCP

LIP PCP
Mean Age of Onset 15.8 mos. 6.2 mos.
Median Age of Onset 13.5 mos. 5 mos.
Overall Mortality 25.7% 85.7%

 

The overall mortality for PCP is 85.7% as compared to 25.7% in the LIP group.
The immune response in these groups differs. PCP is associated with a lympho-
ablative response, while LIP is associated with a lymphoproliferative response.
A greater understanding of the spectrum of disease and knowledge of the natural
history of the various syndromes will allow better predictions of prognosis.
Although not all HIV infected children die early in life, this is an illness that
is unpredictable and is associated with a high rate of morbidity and mortality.

The child is usually the first member of the family that is identified as being
infected. In this situation, screening of the parents and siblings is indicated. In
the majority of cases, the mother is asymptomatic at the time of diagnosis of HIV
infection in her infant. Of the 109 mothers in our patient population, 30% have
subsequently developed AIDS or ARC. Seventeen mothers have died.

This series of patients has offered us the opportunity to evaluate the risk of
an HIV infected pregnant woman delivering an infected infant. Twenty-three HIV
infected women have had 40 subsequent infants after the birth of the index case.
Not every subsequent infant will be infected. We have followed one woman who
has delivered four infected infants, but another mother had an infected infant and
subsequently delivered three uninfected children. Still another had an infected
infant, an uninfected one, and then another infected one. We obviously do not
know what factors cause a mother to pass the infection on to her infant. Of all
the subsequent infants, 52% are infected. This represents a substantial risk for
these women and emphasizes the importance of identifying them so they can
receive appropriate counselling regarding pregnancy. This population may repre-
sent a special population of women, and further studies are underway to deter-
mine the risk of having an infected child in an HIV-positive woman who has not
had previously infected infants.

In conclusion, pediatric HIV infection presents with a broad spectrum of disease
and is associated with a high mortality rate. The majority of children with this
disease are black or Hispanic and reside in the lower socioeconomic areas of the
inner city. It is important to recognize infected children early so that appropriate
instructions for care can be given to the parent and regular medical followup can
be instituted. In addition, with the development of anti-viral drugs, early diag-
nosis and recognition will be imperative, so that early treatment can be given.
Screening of the family is important to identify infected family members and to
give appropriate counselling and education. The HIV-positive woman is at risk
for giving birth to an infected infant. Prevention of perinatal infection will only
be accomplished by prevention of disease in women or by other interventions,
such as drug therapy. Identification of HIV-positive women is important so that
appropriate education and counselling can be provided.

23
NATURAL HISTORY OF HIV INFECTION II
James Oleske, M.D.

Estimates from the CDC suggest that by 1991 there will be 12.5 million
Americans infected with the AIDS virus (Human Immunodeficiency Virus — HIV)
and 250,000 of these will be symptomatic AIDS cases. Based on our experience
and those of others caring for pediatric AIDS cases, by 1991 there may be 10,000
to 20,000 symptomatic HIV infected infants and children in the USA.

Our difficulties in providing care to over 60 active pediatric AIDS cases at
Children’s Hospital of New Jersey in Newark indicate major problems in the near
future. The health care requirements of infants and children infected with HIV
are extensive and include the complex tertiary medical capabilities of a pediatric
hospital and intense psychological services. The care we provide to these children
includes vigorous nutritional support, including placement when necessary of
intravenous catheters, early hospitalization for treatment of possible ‘nfection
episodes, and monthly replacement therapy with intravenous gamma globulin.
Tissue biopsy of lung, lymph nodes, thymus and bone marrow, as well as CAT
scan, gallium scan and esophagoscopy are frequent requirements in the clinical
evaluation of these children. Research and time consuming investigational drug
studies are now being undertaken on our patients. All of these activities — diagnosis,
clinical care, and necessary research—have placed an enormous burden on the
available resources at our children’s hospital. Besides the medical ditemma posed
by AIDS, there is the significant public misunderstanding of this disease with
ongoing stigmatization of patients and their families.

The development of antibody screening tests has substantially reduced (although
not eliminated) the risk of blood transfusion acquired AIDS. It is true that the
majority of cases of AIDS in children is due to perinatal exposure from an infected
mother, but for the next five to six years we must follow a cohort of newborns
who received small blood transfusions in the nursery between 1980 and 1985,
and who are at risk of developing this disease. As pediatricians we must insist
that we have safe blood products for use in children and that we use blood products
appropriately.

It doesn’t take a sophisticated laboratory to make a diagnosis of AIDS. If the
epidemiology and the clinical historic patterns are present, we are comfortable
in Newark making the diagnosis after simple laboratory studies including:
Complete Blood Count (CBC), quantitative immunoglobulin assays, liver func-
tion testing, chest X-rays, and HIV antibody testing. Anemia leads the list of
abnormalities. These children are almost all anemic and most have elevated liver
enzymes.

 

Table 1. Laboratory Findings in Infants and Children

Hypergammaglobulinemia/Hypogammaglobulinemia Anemia

Depresssed T-helper cells Leukopenia

Reversed lymphocyte subset ratio Thrombocytopenia

Depressed lymphocyte responses to mitogens Elevated level of circulating immune complexes
Decreased specific antibody responses Elevated serum transaminase levels

 

The clinical spectrum of illness in children with HIV infection is expanding
as our experience with this disease increases. When we looked carefully at our

24
AIDS and ARC children with failure to thrive, we realized that many of these
infants had problems with the central nervous system. Many had a chronic
encephalopathy. Others had primary HIV infections of the CNS, with failure to
thrive and loss of developmental milestones, the equivalent of the dementia seen
in adults. A child who is otherwise well can present with primary CNS infection
without any other manifestation of AIDS, and even an essentially normal immune
system.

 

Table 2. Neurologic Findings in Children with HIV Infection

Developmental Delay/Loss of Developmental Motor Dysfunction

Milestones Microcephaly
Chronic Encephalopathy Abnormal CT Scan Findings — Cortical
Seizure Disorders Atrophy, Calcifications

 

One of the clinical problems we have had is dealing with the gastrointestinal
manifestations. These children have a variety of GI problems including disten-
sion, diarrhea, inability to eat, and tremendous discomfort. The resultant effect
is marked malnutrition. In seven of fifteen autopsies, we saw cardiovascular abnor-
malities. Three were congestive cardiomyopathies and four arteriopathies. One
case resulted in a fatal coronary artery aneurysm.

Unlike adults, infants with HIV infection will most likely be symptomatic over
the course of their illness. There are some differences between pediatric and adult
AIDS, and these are outlined in the following table.

 

Table 3. Differences between Pediatric and Adult AIDS

. Kaposi’s sarcoma and B cell lymphoma are rare in children

. Hepatitis B infection is less frequent than in adults

Hypergammaglobulinemia is more pronounced in children

. Peripheral lymphopenia is uncommon in children

. Lymphoid interstitial pneumonitis (LIP) is much more common in children

Some children will have normal ratio of helper to suppressor T cells (although quantita-
tively T helper cells are diminished)

Serious bacterial sepsis is a major problem in children

. Dysmorphic features may be found in some children

. Acute mononucleosis-like presentation is rare in children

. Progressive neurologic disease secondary to primary HIV CNS infection is more
pronounced in children

~

 

The final mortality rate is unknown, but with our present program at Children’s
Hospital, we have seen the mortality rate decrease to 35%. With the use of
intravenous gamma globulin therapy, the quality of life for our patients has
improved, with recurrent septic episodes decreasing from 45% in 1983 to 5%
in 1986. We try to provide optimum care to each child, comprehensive rehabili-
tation services, early intervention programs, and psychological support for the
families of our patients. We have learned that HIV probably causes primary infec-
tions not only of the immune system, but also of the CNS, heart, kidneys, and
liver. This primary multisystem/organ infection with the HIV virus as well as
its known secondary opportunistic infections and malignancies present a major
problem in devising therapeutic programs. Educational programs regarding the
real risk of transmission, i.e., blood contaminated needles used in drug addic-
tion, and sexual contact, need to be extended to school age children and hard-to-
reach risk populations. If child-bearing age women at high risk for HIV infection
would avoid pregnancy, we eventually would see no new cases of pediatric AIDS.

25