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HIV INFECTION IN CHILDREN

Presentators : Raja Hasayangan Siregar
Rizki Ananda Lubis (090100011)
Day, Date : Wednesday, 24
nd
April 2013
Supervisor : dr. Supriatmo Sp.A (K)

CHAPTER I
INTRODUCTION

1.1. Background
Varicella or chickenpox is a primary infection of varicella-zoster virus
(VZV), which generally attacks children. Varicella is a disease of the skin
infection that is very contagious. Primary infection by varicella-zoster virus
causing varicella (chicken pox).
Varicella can infect all age groups, including neonates, but nearly 90% of
cases concerning children under the age of 10 years, and most at the age of 5 to 9
years. Transmission of varicella occurred since before the rash came out until a
scab.
Varicella generally have mild symptoms, and the disease can heal itself with a
very rare complication. However, in children with decreased immune status such
as children who are suffering from leukemia, HIV, or who is receiving
immunosuppressant treatment, will easily get severe complications and death.
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Humans are infected when the virus comes in contact with the mucosa of the
upper respiratory tract or the conjunctiva. Transmission occurs from patients with
varicella through direct contact, air, or contact with varicella zoster lesions.
Infection can also occur in the fetus in the womb, because the virus can cross the
placenta during fetal mothers infected by the virus.
Human Immunodeficiency virus (HIV) has been a major threat since the
past 30 years, after the first infection was identified during 1981, the number of
children infected with HIV has increased dramatically in developing countries as
the number of HIV-infected women of childbearing age has risen.
In developed countries, universal prenatal HIV tests has been
recommended to obstetricians since 1995. However, this tests were not mandatory
in every of those countries. Before prenatal testing was common, diagnosing HIV
infection in a woman after diagnosing it in her child was not unusual, and the
diagnosis of acquired immunodeficiency syndrome (AIDS) in a previously
healthy child was not rare.
Before 1985, one way in which children were infected was due to
transfusion of blood products. However, improved screening tests have eliminated
such transmission in developed countries.
Vertical transmission of HIV from mother to child is the main route by
which childhood HIV infection is acquired, the risk of perinatal acquisition is 25-
40% without intervention
1
. Perinatal transmission can occur in utero, during
peripartum period, and from breast feeding.
Although 2 strains of HIV have currently been identified, most patients
who have AIDS are positive with HIV type 1 (HIV-1) or are positive for both
HIV-1 and HIV type-2 (HIV-2). HIV-2 infection is most commonly observed in
West Africa.
A variety of signs and symptomps should alert the clinician to the
possibility of HIV infection in a child. The presentations include recurrent
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bacterial infections, unrelenting fever, unrelenting diarrhea, unrelenting thrush,
recurrent pneumonia, chronic parotitis, generalized lymphadenopathy, delay in
development with failure to thrive, and significant pruritic dermatoses.
Mucotaneous eruptions may be the first sign of HIV infection and may vary in
presentation, depending on the childs immune status.

1.2. Objective
The aim of this study is to explore more about the theoritical aspects on
Varicella and HIV infection, and to integrate the theory and application of
Varicella and HIV infection cases in daily life.













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CHAPTER II
LITERATURE REVIEW

2.1. Varicella Infection
2.1.1. Definition
Varicella or chicken pox is a disease caused by infection of primary
varicella-zoster virus (VZV), which generally occurs in children. Varicella in
children with immunocompromaised may have symptoms such as bleeding,
progressive and a spread of the infection that causes poor prognosis.
2.1.2. Etiology
Varicella or chicken pox is caused by varicella-zoster virus (VZV).
Varicella-zoster virus is one of the 8 types of herpes virus of the family
Herpesviridae, which can infect humans and primates, and an alpha-herpesviridae
DNA virus, has 125,000 base pairs containing 70 genes.
2.1.3. Epidemiology
In western countries, the incidence of varicella depending on the season
(winter and early spring), In Indonesia, although studies have not been done,
presumably viral disease attack in the transitional seasons, the rainy season to
summer or vice versa. Based on data from the polyclinic Pediatrics Hospital Cipto
Mangunkusumo (IKA-RSCM) in the last 5 years without a recorded 77 cases of
varicella complications.
Household transmission rate is 80% to 90%, more contact by chance, such
as school classrooms Exposure, along with an attack rate of 30% or less.
2.1.4. Pathogenesis
Varicella is highly contagious, especially through direct contact, droplets
or aerosols from vesicular lesions of the skin or through respiratory secretions,
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and rarely by indirect contact. Prodormal viremia occurs during the transmission
of the virus can occur so that the intrauterine fetus or through blood transfusions.
Patients can transmit the disease for 24 to 48 hours before skin lesions arise, until
all lesions arising crusting / scab usually 7 to 8 days.

Viral replication occurs in the local lymph nodes for 2 to 4 days followed
by primary viremia occurs 4 to 6 days after inoculation. The virus then replicates
in the liver, spleen, and other organs. The virus re-released into the blood
circulation (secondary viremia). At the secondary viremia occurs mainly spread of
virus particles into the skin, this process occurs approximately 14 to 16 days after
contact. After the secondary viremia, there arose a typical vesicular lesions.
Latent VZV in cells in the dorsal root ganglia of all individuals who
experience primary infection. Reaktivasinya cause localized vesicular rash that
usually involves the deployment dermatomes of the sensory nerves, the ganglia
induced necrotic changes associated, sometimes extends to the posterior horn
visceral and histopathological lesions of herpes zoster. Varicella humoral and
cellular immunity to form highly protective against re-infection.
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2.1.5. Clinical Symptoms
In the prodromal stage, prodromal symptoms appear after 14 to 15 day
incubation period, the incidence of skin rash accompanied by fever and malaise
are not so high. In older children and adults of the rash preceded by fever for 2 to
3 days in advance, chills, malaise, headache, anorexia, back pain, and sometimes
there is pain throat and cough.
In stage eruptions, skin rash appears on the face and head, quickly spread
to the body and extremities. More rashes on the body are covered and are rarely
found on the soles of the feet and hands. Spread of varicella lesions is centrifugal.
Salient features is the rapid change from reddish to macular papules, vesicles,
pustules, and eventually became crusting. This change occurs only within 8 to 12
hours. Overview of typical vesicles, superficial, thin walls and looks like water
droplets, section 2 to 3mm elliptical with axes parallel to the line of skin folds.
Vesicle fluid clear at the outset, and quickly became turbid due with inflammatory
cells and become pustules. Lesions then dries that starts from the center and
eventually form a crust. Crusting will take within 1 to 3 weeks depending on
which skin disorders. If there are complications such as secondary infections can
occur scarring.

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Children with severe immune disorders, especially those with HIV
infection, may suffer from a chronic skin disease, unusual or repetitive, retinitis,
or central nervous system disease without a rash. In children with
immunocompromaised, had more lesions and often with hemorrhagic base, and
the healing period takes almost 3 times longer than in immunocompetent children.
Immunocompromaised children with progressively more susceptible than
immunocompetent children. Severe varicella characterized by the eruption of
lesions and high fever continuously for the first 2 weeks.
On research in Philiphina immunocompromaised said some children who
suffer from acute varicella varicella will be with DIC (Disseminated Coagulation
Intravscular) and growing rapidly, and severe if it does not receive treatment, seen
in their patients were describing severe skin eruptions and died within 48 hours.
2.1.6. Diagnosis
Varicella diagnosis can be established based on typical clinical symptom
picture. Typical features that include:
1. Appears after a short period and light prodormal.
2. Lesions clustered mainly in the central part.
3. Rapid changes of macular lesions, vesicles, pustules, crusting up.
4. The presence of all forms of skin lesions at the same time in the same area.
5. There are oral mucosal lesions
Rapid laboratory diagnosis of VZV is important in patients with high risk
and can be refined by immunohistochemical staining cells directly from skin
lesions. Multinucleated giant cells can be detected with nonspecific staining, but
often there are false negative results, and this method does not distinguish
between HSV and VZV infections. Definitive diagnosis requires the discovery of
VZV infection infectious virus using tissue culture. VZV IgG antibody test is
useful for determining the immune status of the individual clinical history of
varicella is unknown. Serum IgA and IgM antibodies can be detected in the first
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and second days after the rash. Laboratory tests that may be done include virus
isolation (3 to 5 days), PCR, elisa, immunofluorescence techniques Fluoresecent
Antibody to Membrane Antigen (FAMA), which is the gold standard.
2.1.7. Varicella in immunocompromaised
In patients with immunocompromaised, varicella can be severe and even
cause death. Complications occur due to an immune response that fails to address
the replication and spread of the virus.
Varicella in children with immunocompromaised is a cause of significant
morbidity and mortality. Children with acute leukemia, lymphoma, AIDS, and
children with corticosteroid treatment were delayed in the high risk.
Cases with immune disorders or who receive corticosteroids can cause mild to
severe symptoms of bleeding and fatal (purpura malignant). In cases of fulminant
varicella infection and the possibility of malignant purpura capillary endothelial
cells become a major factor. Endothelial cell damage is caused disseminated
intravascular coagulation (DIC) and thrombotic purpura.
2.1.8. Complications
Varicella-zoster virus (VZV) infection is a highly contagious disease, but
can be self-limiting in healthy children. On the other hand, children with varicella
immunocompromaised risk of suffering from a severe, prolonged, and difficult to
heal. This is because the patient immunocompromaised difficult to predict the
degree of severity of the disease. Treatment more quickly provide a good
prognosis.
Secondary bacterial infection, usually due to S. Aureus or Streptococcus
pyogenes, is the most common complication of varicella. Cellulitis, lymphadenitis
and subcutaneous abscesses are also common.
Children who are exposed to varicella after organ transplantation are also
at risk for progressive VZV infection. Children with low long-term steroid therapy
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usually does not have any complications, but deadly varicella occur in patients
who are on high doses of steroids. Untreated severe varicella be deadly in children
with immuno deficiency congenital disorders, especially involving cellular
immunity.
In rare circumstances, varicella during pregnancy will cause congenital
varicella in children, which is accompanied by an unusual skin defects, limb
atrophy, microcephaly, ocular defects, and injury to the autonomic nervous
system. Babies born within 1 day after or 2 days before the onset of maternal
varicella, varicella is likely to get progressively. Symptoms such as bleeding,
petechiae, purpura, epistaxis, hematuria, gastrointestinal bleeding, and DIC due to
complications such as thrombocytopenia.
2.1.9. Treatment
In healthy children, varicella is generally mild and self-limiting, sufficient
given symptomatic treatment. At the local skin lesions can be lotio calamine. To
reduce the itching can be a cold compress, bathe regularly or with antihistamine.
Antipyretic rarely necessary. Salicylate is not recommended because it deals with
the onset of Reye's syndrome, whereas acetaminophen tend to give the opposite
effect, do not relieve symptoms even prolong illness. Nails cut short and clean so
that no secondary infection and scarring scratching. In case of secondary infection
are given antibiotics.
American Academy of Pedriatics not recommend routine administration of
acyclovir in healthy children, but for children with immunocompromaised
(including those receiving high-dose corticosteroid therapy) the recommended
intravenous acyclovir. In patients immunocompromaised, giving acyclovir shown
to reduce morbidity and mortality when administered within the first 24 hours
after the onset of rash. Dose oral acyclovir is 20mg/kgBB per time (maximum
dose 800 mg) administered 4 times daily for 5 days and start in the first 24 hours
after the onset of rash, while acyclovir is generally given intravenously at a dose
of 500mg/m2 every 8 hours for 7 to 10 days.
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2.2. Human Immunodeficiency Virus Infection
2.2.1. Definition
Human immunodeficiency virus in an infection that affects the cells of the
immune system, including helper T lymphocytes (CD4 lymphocytes), monocytes
and macrophages. The functions ofthese cells are diminished by HIV infection,
with profound affects towards both humoral and cell-mediated immunity. In the
absence of treatment, HIV infection causes deterioation of the immune system,
leading to conditions that is known as acquired immunodeficiency syndrome
(AIDS), and severe complications due to vulnerability towards infections.
2.2.2. Etiology
HIV infectino is caused by a complex member of the Lentivirus genus of
the Retroviridae family. HIV-1 is the most common cause of HIV infection in the
South east Asia. HIV-2 disease progresses more slowly than HIV-1 disease, and
HIV-2 is less transmissible than HIV-1
HIV-1 subtypes differ by geographic region. HIV-1 non-B subtypes are
the most dominant is South east Asia and Africa. The high transmission rate from
these countries to Europe has increased the diversity of subtypes in Europe. In
United States however, HIV-1 B subtypes are the most dominant types.
Vertical transmission of HIV from mother to child is the main route by
which childhood HIV infection is acquired, and the risk of this perinatal
acquisition is 25%.
2.2.3. Epidemiology
The World health organization estimates that approximately 2.5 million
children were living with HIV infection as of 2009. In 2009 alone, 370,000
children were newly infected. This is a drop of 24 % from 5 years earlier.
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About 0.9% of cases of HIV infection occur in children younger than 1
years old and 1.4% in children younger than 4 years. Incidence peaks in those
whose age group are within20-29years old.
According to the national survey, the percentage of cases caused by
mother to baby transmission as a risk factor is 2.7 %. This figure has decreased
more than 40% from the past respective years since 1991.
The WHO estimates that over 33 million individuals are infected with HIV
worldwide, and 90% of them are in developing countries. HIV has infected 4.4
million children and has resulted in the deaths of 3.2 million. Each day, 1800
childrenthe vast majority newbornsare infected with HIV. Approximately 7%
of the population in sub-Saharan Africa is infected with HIV; these individuals
represent 64% of the world's HIV-infected population. Furthermore, 76% of all
women infected with HIV live in this region.
Although the annual number of new HIV infections has been steadily
declining since the late 1990s, the epidemics in Eastern Europe and in Central
Asia continue to grow; the number of people living with HIV in these regions
reached an estimated 1.6 million in 2005an increase of almost 20-fold in less
than 10 years.
2
The overwhelming majority of these people living with HIV are
young; 75% of infections reported between 2000 and 2004 were in people
younger than 30 years. In Western Europe, the corresponding percentage was
33%.
The magnitude of the AIDS epidemic in Asia is significant. The
seroprevalence rate in pregnant women is already 2%, and the vertical
transmission rate is 24% without breastfeeding. Indian mothers infected with HIV
routinely breastfeed and have transmission rates as high as 48%.
Globally, children outside the United States are not faring as well. Every
day, 1400 children become HIV positive and 1000 children die of HIV-related
causes. An estimated 2.5 million children worldwide younger than 15 years are
living with HIV/AIDS. In sub-Saharan Africa alone, 1.9 million children are
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living with HIV/AIDS and more than 60% of all new HIV infections occur in
women, infants, or young children. As of 2007, 90% of the newly infected
children are infants who acquire HIV from their infected mothers. Alarmingly,
90% of babies who acquire the disease from infected mothers are found in sub-
Saharan Africa. The prevalence of HIV infection among undernourished children
has been estimated to be as high as 25%.
In 2004, more than half a million children younger than 15 years died from
HIV/AIDS. In 2006, this number decreased to 380,000. In 2002, HIV/AIDS was
the seventh leading cause of mortality in children in developing countries. The
disease progresses rapidly in approximately 10-20% of children who are infected,
and they die of AIDS by age 4 years, whereas 80-90% survive to a mean age of 9-
10 years.
A 2006 South African study estimated that HIV/AIDS is the single largest
cause of infant and childhood deaths in rural South Africa.

HIV/AIDS is now
responsible for 332,000 child deaths in sub-Saharan Africa, almost 8% of all child
deaths in the region.
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The results of one study noted that pneumonia and malnutrition are highly
prevalent and are significantly associated with high rates of mortality among
hospitalized, HIV-infected or HIV-exposed children in sub-Saharan Africa. Other
independent predictors of death were septicemia, Kaposi sarcoma, meningitis, and
esophageal candidiasis for HIV-infected children; and meningitis and severe
anemia for inpatients exposed to HIV. These results stress the importance of
expediently establishing therapeutic strategies in African pediatric hospitals.
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2.2.4. Pathogenesis and Pathophysiology
The pathogenesis of HIV is basically a struggle between HIV replication and the
immune responses of the patient, via cell-mediated and immune-mediated
reactions. The HIV viral burden directly and indirectly mediates CD4+ T-cell
destruction.
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When the mucosa serves as the portal of entry for the HIV, the first cells to
be infected are the dendritic cells. These cells are in charge of collecting and
processing antigens introduced from the periphery and transporting them to the
lymphoid tissue. The HIV does not infect the dendritic cell but it binds to its DC-
SIGN surface molecule, which allows the virus to survive until it reaches the
lymphatic tissue. In the lymph node, the HIV selectively binds to cells expressing
CD4 molecules on their surface, primarily helper T lymphocytes (CD4 cells) and
cells of the monocyte-macrophage lineage.
Another cells such as microglia, astrocytes, oligodendroglia, and placental
tissue containing villous Hofbauer cells, may also be infected by HIV. Usually,
CD4 lymphocytes, recruited to respond to viral antigen, migrate to the lymph
nodes where they become activated and proliferate, making them highly
susceptible to HIV infection. This antigen-driven migration and accumulation of
CD4 cells within the lymphoid tissue may contribute to the generalized
lymphadenopathy characteristic of the acute retroviral syndrome in adults and
adolescents. When the HIV replication reaches a threshold (usually within 36 wk
from the time of infection), a burst of plasma viremia occurs. This intense viremia
cause flulike symptoms (i.e., fever, rash, lymphadenopathy, and arthralgia) in 50
70% of infected adults. With establishment of a cellular and humoral immune
response within 24 mo, the viral load in the blood declines substantially, and
patients enter a phase characterized by a lack of symptoms and a return of CD4
cells to only moderately decreased levels.
Table 2.2.4. Cells Infected by HIV
System Cell
Hematopoietic T-cells (CD4+ OR
CD 8+)

Macrophages/monocytes
Dendritic cells
Fetal thymocytes and thymic
epithelium
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B-cells
NK cells
Megakaryotic cells
Stem cells
Central Nervous

Microglia Capillary endothelial cells
Astrocytes
Oligodendrocytes
Large Intestine Columnar epithelium
Other

Kupfer cells (liver
Synovial cells
Placental tophoblast cells
Adapted from Levy L.A. Microbiological Reviews, 57:183-289, March 1993
These cells may be destroyed by multiple mechanisms: HIV-mediated
single cell killing, formation of multinucleated giant cells of infected and
uninfected CD4 cells (syncytia formation), virus-specific immune responses,
superantigen-mediated activation of T cells (rendering them more susceptible to
infection with HIV), and programmed cell death (apoptosis). Viral replication in
monocytes, which can be infected productively yet resist killing, explains their
role as reservoirs of HIV and as effectors of tissue damage in organs such as the
brain.
Cell-mediated and humoral responses occur early in the infection. The
CD8 T cells play an important role in containing the infection. HIV-specific
cytotoxic T lymphocytes (CTLs) develop against both the structural (i.e., ENV,
POL, GAG) and regulatory (e.g., tat) viral proteins. The CTL cells appear at the
end of the acute retroviral infection as the viral replication is controlled. The CTL
cells control the infection by killing HIV-infected cells before new viruses are
produced and by secreting potent antiviral factors that compete with the virus for
its receptors (e.g., CCR5). Neutralizing antibodies appear later during the
infection and seem to help in the continued suppression of viral replication during
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clinical latency. There are at least two possible mechanisms that control the
steady-state viral load level during the chronic clinical latency. One mechanism
may be the limited availability of activated CD4 cells which prevent further
increase in viral load due to a set point (i.e., controlled) replication. The other
mechanism, the immune-control, suggests that the development of active immune
response (whose magnitude is controlled by the amount of the viral antigen) limits
the viral replication at a steady state. There is no general consensus about which
of these two mechanisms is more important. The CD4cell limitation mechanism
accounts for the effect of antiretroviral therapy, whereas the immune-control
mechanism emphasizes the importance of immune-modulation treatment (e.g.,
cytokines, vaccines) to increase the efficiency of the immune response, which, in
turn, slows the disease progression.
A group of cytokines, such as tumor necrosis factor (TNF), TNF,
interleukin 1 (IL-1), IL-3, IL-6, interferon-, granulocyte-macrophage colony-
stimulating factor (GM-CSF), and macrophage colony-stimulating factor, play an
integral role in upregulating HIV expression from a state of quiescent infection to
active viral replication. Other cytokines such as interferon (INF), INF-, and
transforming growth factor D exert a suppressive effect on HIV replication. The
interactions among these cytokines influence the concentration of viral particles in
the tissues. Plasma concentrations of cytokines need not be elevated for them to
exert their effect, because they are produced and act locally in the tissues. Thus,
even during states of apparent immunologic quiescence, the complex interaction
of cytokines sustains a constant level of viral expression, particularly in the lymph
nodes.
Commonly the phenotypic HIV isolated during the clinical latency period
grows slowly in culture and produces low titers of reverse transcriptase. These
isolates are called nonsyncytium-inducing (NSI) viruses, which use CCR5 as
their co-receptor. By the late stages of the clinical latency, the isolated virus is
phenotypically different. It grows rapidly and to high titers in culture and it uses
CXCR4 as its co-receptor. These isolates are called syncytium-inducing (SI)
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viruses. The switch from NSI to SI increases the capacity of the virus to replicate,
to infect a broader range of target cells (CXCR4 is more widely expressed on
resting and activated immune cells), and to kill T cells more rapidly and
efficiently. As a result, the clinical latency phase is over and progression toward
AIDS is noted. The progression of disease is related temporally to the gradual
disruption of lymph node architecture and degeneration of the follicular dendritic
cell network with loss of its ability to trap HIV particles. This frees the virus to
recirculate, producing high levels of viremia and an increased disappearance of
CD4 T cells during the later stages of disease.
HIV-infected children have changes in the immune system that are similar
to those in HIV-infected adults. CD4 cell depletion may be less dramatic because
infants normally have a relative lymphocytosis. Lymphopenia is relatively rare in
perinatally infected children and is usually only seen in older children or those
with end-stage disease.
2.2.5. Clinical Manifestations
The clinical manifestations of HIV infection vary widely among infants, children,
and adolescents. In most infants, physical examination at birth is normal. Initial
symptoms may be subtle, such as lymphadenopathy and hepatosplenomegaly, or
nonspecific, such as failure to thrive, chronic or recurrent diarrhea, interstitial
pneumonia, or oral thrush, and may be distinguishable only by their persistence.
Symptoms found more commonly in children than adults with HIV infection
include recurrent bacterial infections, chronic parotid swelling, lymphocytic
interstitial pneumonitis (LIP), and early onset of progressive neurologic
deterioration.
Table 2.2.5. Clinical Finding Suggestive for HIV

Highly suggestive for

Suggestive for HIV
Likely to be evidence
of HIV infection but
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HIV infection infection common in both HIV-
infected and
uninfected children
Esophageal candidiasis
Herpes zoster
Invassivesamonella
infection
Pneumocystis jirovecii
pneumonia
Extrapulmonary
cryptococcosis
Kaposi sarcoma
Recurrent severe bacterial
infection
Persistent or recurrent oral
thrush
Parotid enlagement
Generalized
lymphadenopathy
Hepatosplenomegaly
Persistent orrecurrent
fever
Neurologic dysfunction
sPersistent generalized
dermatitis
Otitis media- persistent
or recurrent
Diarrhea persistent or
recurrent
Severe Pneumonia
Tuberculosis
Failure to thrive

2.2.6. Diagnostic
There are several laboratory tests to diagnose hiv infection. It can be devided into
antibody and virologic test. HIV rapid test, HIV ELISA and Western Blot are kind
of serologic test. HIV-1 RNA PCR. HIV-1 RNA PCR, another important
virologic test, is commonly used to monitor response to HIV treatment.
Table 2.2.6. Common HIV Diagnostic Tests
Antibody Virologic
HIV rapid test HIV-1 DNA PCR
HIV ELISA (also called EIA) HIV-1 RNA PCR (viral load)
Western blot Ultrasensitive p24 antigen
assay test
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HIV culture

A. Antibody Test
Antibody test is used to diagnose HIV infection. This category of test
includes HIV rapid tests, ELISA, and Western blot. Antibody tests can detect the
antibodies that are produced during the immune response to HIV. Like most lab
tests, they can yield falsenegative and false-positive results. False-negative tests
occur when HIV-infected individuals do not produce detectable antibodies, such
as during the early, acute phase of the infection (the preantibody, or window,
period) and the very late stages of infection (when immune suppression is severe
and antibodies are no longer being produced in response to HIV
infection).Usually, individuals produce antibodies within 6 weeks of infection,
and almost all infected individuals have detectable antibodies by 12 weeks
postinfection.

The other primary cause of false-negative antibody tests is severe
immunosuppression. During the very late stages of HIV-infection, antibody levels
can fall so far as to become undetectable. When a false negative is suspected in
the presence of severe clinical symptoms, further testing is required. One of the
most important diagnostic limitations of antibody tests occurs in infants younger
than 18 months. During pregnancy, HIV-infected mothers passively transfer
immunoglobulin G HIV antibody to the infant through the placenta.

B. Virologic Tests
HIV-1 RNA PCR. HIV-1 RNA PCR, another important virologic test, is
commonly used to monitor response to HIV treatment. Whereas DNA PCR is a
qualitative test providing positive or negative results, RNA PCR tests are
quantitative and indicate how much HIV is in the blood. For this reason, RNA
PCR is also known as the viral loadmand represents the number of copies of HIV
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per milliliter. RNA PCR is also an accurate method of HIV diagnosis in young
infants (>10,000 copies/mL is considered diagnostic). RNA PCR sensitivity and
specificity are similar to those of DNA PCR in this group (nearly 100% by 6
weeks of age for exposed, nonbreast-feeding infants).

Ultrasensitive p24 antigen assay. Another laboratory test that directly
detects HIV in the bloodstream is the p24 antigen test. The antigen p24 is a major
core protein of HIV that can be found either free in the bloodstream of HIV-
infected people or bound to anti-p24 antibody.

2.2.7. Clinical Staging On HIV Infection
Clinical staging is for use where HIV infection has been confirmed (i.e.
serological and/or virological evidence of HIV infection). It is informative for
assessment at baseline or entry into HIV care and can also be used to guide
decisions on when to start CPT in HIV-infected children and other HIV-related
interventions, including when to start, switch or stop ART in HIV-infected
children, particularlyin situations where CD4 is not available.

Table 2.2.7. Clinical Stage On HIV Infection
Children less than 15 years old Children greater than 15 years old and
adults
CLINICAL STAGE 1
Asymptomatic
Persistent.generalized
lymphadenopathy
CLINICAL STAGE 1
Asymptomatic
Persistent.generalized
lymphadenopathy
CLINICAL STAGE 2
Unexplained persistent
hepatosplenomegaly
Papular pruritic eruptions
Extensive wart virus infection
CLINICAL STAGE 2
Unexplained moderate weight loss
(<10% of presumed or
measured body weight)
Recurrent respiratory tract infections
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Extensive molluscum contagiosum
Fungal nail infections
Recurrent oral ulcerations
Unexplained persistent parotid
enlargement
Lineal gingival erythema
Herpes zoster
Recurrent or chronic upper respiratory
tract infections (otitis media,
otorrhoea, sinusitis or tonsillitis)
(sinusitis, tonsillitis, otitis
media and pharyngitis)
Herpes zoster
Angular cheilitis
Recurrent oral ulceration
Papular pruritic eruptions
Seborrhoeic dermatitis
Fungal nail infections
CLINICAL STAGE 3
Unexplained moderate malnutrition
not adequately responding to
standard therapy
Unexplained persistent diarrhea (14
days or more)
Unexplained persistent fever (above
37.5C intermittent or
constant, for longer than one month)
Persistent oral candidiasis (after 6-8
weeks of life)
Oral hairy leukoplakia
Acute necrotizing ulcerative gingivitis
or periodontitis
Lymph node tuberculosis
Pulmonary tuberculosis
Severe recurrent bacterial pneumonia
Symptomatic lymphoid interstitial
pneumonitis
Chronic HIV-associated lung disease
including brochiectasis
CLINICAL STAGE 3
Unexplained severe weight loss
(>10% of presumed or measured
body weight)
Unexplained chronic diarrhea for no
longer than one month
Unexplained persistent fever (above
37.5C intermittent or
constant, for longer than on month)
Persistent oral candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis
Severe bacterial infections (such as
pneumonia, empyema,
pyomyositis, bone or joint infection,
meningitis or bacteraemia)
Acute necrotizing ulcerative
stomatitis, gingivitis or periodontitis
Unexplained anaemia (<8 g/dl),
neutropaenia (<0.5 x 109 per
litre) and/or chronic thrombocytopaenia
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Unexplained anaemia (<8g/dl),
neutropaenia (<0.5 x 109 per litre)
and or chronic thrombocytopaenia (<50
x 109 per litre)
(<50 x 109 per litre)
CLINICAL STAGE 4
Unexplained severe wasting, stunting
or severe malnutrition not
responding to standard therapy
Pneumocystis pneumonia
Recurrent severe bacterial infections
(such as empyema, pyomyositis,
bone or joint infection or meningitis
but excluding pneumonia)
Chronic herpes simplex infection
(orolabial or cutaneous of more
than one months duration or visceral at
any site)
Extrapulmonary tuberculosis
Kaposi sarcoma
Oesophageal candidiasis (or
candidiasis of trachea, bronchi or lungs)
Central nervous system toxoplasmosis
(after one month of life)
HIV encephalopathy
Cytomegalovirus infection: retinitis or
cytomegalovirus infection
affecting another organ, with onset at
age older than one month
Extrapulmonary cryptococcosis
(including meningitis)
Disseminated endemic mycosis
CLINICAL STAGE 4
HIV waste syndrome
Pneumocystis pneumonia
Recurrent severe bacterial pneumonia
Chronic herpes simplex infection
(orolabial, genital or anorectal
of more than one months duration or
visceral at any site)
Oesophageal candidiasis (or
candidiasis of trachea, bronchi or
lungs)
Extrapulmonary tuberculosis
Kaposis sarcoma
Cytomegalovirus infection (retinitis or
infection of other organs)
Central nervous system toxoplasmosis
HIV encephalopathy
Extrapulmonary cryptococcosis
including meningitis
Disseminated non-tuberculous
mycobacterial infection
Progressive multifocal
leukoencephalopathy
Chronic cryptosporidiosis
Chronic isosporiasis
Disseminated mycosis
(extrapulmonary histoplasmosis or
22

(extrapulmonary histoplasmosis,
coccidiomycosis)
Chronic cryptosporidiosis
Chronic isosporiasis
Disseminated non-tuberculous
mycobacterial infection
Cerebral or B-cell non-Hodgkin
lymphoma
Progressive multifocal
leukoencephalopathy
Symptomatic HIV-associated
nephropathy or HIV-associated
cardiomyopathy
Some additional specific conditions can
also be included in regional
classifications
(such as reactivation of American
trypanosomiasis [meningoencephalitis
and/or myocarditis] in the WHO
Region of the Americas, penicilliosis in
Asia
and HIV-associated rectovaginal fistula
in Africa).
coccidiomycosis)
Recurrent septicaemia (including non-
typhoidal Salmonella)
Lymphoma (cerebral or B-cell non-
Hodgkin)
Invasive cervical carcinoma
Atypical disseminated leishmaniasis
Symptomatic HIV-associated
nephropathy or symptomatic
HIV-associated cardiomyopathy

Source: WHO case definitions of HIV for surveillance and revised clinical staging
and immunological classification of HIV-related disease in adults and children,
2007. Available at http://www.who.int/hiv/pub/guidelines/en/.

Table. 2.2.7. Stage of HIV Infection Base on CD4+ Count
HIV-associated <11 months 12-35 36-59 >5 years
23

immunodeficiency (% CD4+) months (%
CD4+)
months (%
CD4+)
months (%
CD4+)
None or not
significant
>35 >30 >25 >500
Mild 30-35 25-30 20-25 350-499
Advanced 25-29 20-24 15-19 200-349
Severe <25 <20 <15 <200 or
<15%

Source: World Health Organization, Antiretroviral Therapy of HIV Infection in
Infants and Children in Resource-Limited Settings: Towards Universal Access -
Recommendations for a Public Health Approach, August 7, 2006.

a. Clinical Latency/Asymptomatic Disease (Clinical Stage 1)
Although patients recently infected with HIV usually experience a
clinically latent period of years between HIV infection and clinical signs and
symptoms of AIDS, evidence of HIV replication and host immune system
destruction exists from the onset of infection. Early during this time, referred to as
Clinical Stage 1 , the immune system produces antibodies in an attempt to protect
itself from HIV. This is when the viral set point is established. The viral load of
the set point can be used to predict how quickly disease progression will occur.
People with higher viral load set points tend to exhibit more rapid disease
progression than those with lower viral load set points. During latency, HIV-
infected patients may or may not have signs and symptoms of HIV infection
though persistent lymphadenopathy is common. In HIVinfected adults, this phase
may last 810 years. The HIV enzyme-linked immunosorbent assay and Western
blot or immunofluorescence assay will be positive. The CD4+ count is greater
than 500 cells/L in children over 5 years of age.



24

b. Clinical Stage 2
HIV-infected people may appear to be healthy for years, and then minor signs and
symptoms of HIV infection begin to appear. They may develop candidiasis,
lymphadenopathy, molluscom contagiosum, persistent hepatosplenomegaly,
popular pruritic eruptions, herpes zoster, and/or peripheral neuropathy. The viral
load increases, and the CD4+ count falls is between 350-499/ uL in children older
than 5 years. Once patients are in this stage they remain in stage 2. They can be
reassigned stage 3 or 4 if a condition from one of those occurs, but they cannot be
reassigned to Clinical Stage 1 or 2 if they become asymptomatic.

c. Clinical Stage 3
HIV-infected patients with weakened immune systems can develop life-
threatening infections. The development of cryptosporidiosis, pulmonary and
lymph node tuberculosis, wasting, persistent fever (longer than one month),
persistent candidasis, recurrent bacterial pneumonia, and other opportunistic
infections is common. These patients may be wasting, or losing weight. Their
viral load continues to increase, and the CD4+ count falls to less than 200-349
cells/L in children older than 5 years.

d. Clinical Stage 4
Patients with advanced HIV disease, or AIDS, can continue to develop new
opportunistic infections, such as Pneumocystis jirovecii pneumonia (formerly
Pneumocystis carinii pneumonia), cytomegalovirus infection, toxoplasmosis,
Mycobacterium avium complex, cryptococcal meningitis, progressive multifocal
leukoencephalopathy, Kaposi sarcoma and other infections that commonly occur
with a severely depressed immune system. The viral load is very high, and the
CD4+ count is less than 200 cells/L in children older than 5 years. At this point
in the disease course death can be imminent.

2.2.8. Treatment
25

Table 2.6 Indications for initiation of antiretroviral therapy in children infected
with human immunodeficiency virus (HIV)

Age Criteria Reccomendation
<12 months Regardless of clinical symptoms,
immune status, or viral load
Treat
1 - <5 years


AIDS or significant HIV-related
symptoms1
CD4 <25%, regardless of symptoms or
HIV RNA level2
Asymptomatic or mild symptoms
CD4 25%
HIV RNA >100,OOO copies/mL
Asymptomatic or mild symptoms3
CD4 25%
HIV RNA <100,000 copies/mL
Treat
Treat

Consider

Defer
5 years AIDS or significant HIV-related
symptoms1
CD4 <350 cells/mm3
Asymptomatic or mild symptoms and
CD4 350 cells/mm and
HIV RNA 100,000 copies/mL
Asymptomatic or mild symptoms3 and
4
CD4 350 cells/mm] and
HIV RNA <100,000 copies/mL
Treat
Treat
Consider

Defer

Fixed-dose formulations for children became available in late 2005; they
include d4T/3TC/NVP in different strengths, although they are not yet approved
26

by stringent regulatory authorities. FDC of standard first and second line ARV
regimens are urgently neededfor younger children.

The preferred option when choosing a first-line regimen for infants and
children is two nucleoside reverse transcriptase inhibitors (NRTIs) plus one non-
nucleoside reverse transcriptase inhibitor (NNRTI). These drugs prevent HIV
replication by inhibition of the action of reverse transcriptase, the enzyme that
HIV uses to make a DNA copy of its RNA.

Regimen of 2 NRTI plus 1 NNRTI:
AZT b + 3TCc + NVPd/ EFVe
d4T b + 3TCc + NVPd /EFVe
ABC + 3TCc + NVPd/ EFVe


In addition, they preserve a potent new class (i.e. protease inhibitors [PIs])
for the second line. The disadvantages include different half-lives, the fact that a
single mutation is associated with resistance to some drugs (e.g. lamivudine
[3TC], NNRTIs), and, in respect of the NNRTIs, a single mutation can induce
resistance to all currently available drugs in the class.

Active components of these regimens may include a thymidine analogue
NRTI (i.e. stavudine [d4T], zidovudine [AZT]) or a guanosine analogue NRTI
(i.e. abacavir [ABC]), combined with a cytidine analogue NRTI, (i.e. lamivudine
[3TC] or emtricitabine [FTC]) and an NNRTI (i.e. efavirenz [EFV] or nevirapine
[NVP]).
A caveat is that EFV is not currently recommended for use in children
under 3 years of age because of a lack of appropriate dosing information, although
these matters are under study. For such children, consequently, NVP is the
recommended NNRTI. Additional concerns about NNRTIs as components of
first-line regimens relate to their use in adolescents , these include the teratogenic
27

potential of EFV in the first trimester of pregnancy and the hepatotoxicity of NVP
in adolescent girls with CD4 absolute cell counts >250/mm3. The available data
on infants and children indicate a very low incidence of severe hepatotoxicity for
NVP without association with CD4 count.

2.2.9. Education
Educating parents regarding the importance of compliance with prescribed
medications and health care visits is a major challenge. Patients should be
educated regarding the transmission of HIV. Increasing their awareness of the
mechanism and consequences of HIV transmission is important. Safe social
interactions that do not expose people to an increased risk for HIV transmission
should also be emphasized.
2.2.10. Complication
Many people living with human immunodeficiency virus (HIV)/AIDS acquire
diseases that also affect otherwise healthy people. In such cases, HIV-infected
patients may have a more severe disease course than uninfected people or may
develop symptoms that uninfected people do not. However, HIV-infected people
are also susceptible to opportunistic infections (OIs), which are infections caused
by organisms that in a healthy. Not only OIs, HIV also can cause malnutrition and
wasting syndromes to the patient. Therere several case that usually found in HIV
infection:

1) Hepatitis
Hepatitis C virus (HCV) is a significant public health concern; it affects 3.9
million persons in the United States and an estimated 170 million persons
worldwide. Those persons with repeated exposure to blood or blood products are
at risk for both HIV and HCV infection. An estimated 60%90% of persons with
hemophilia and 50%90% of injection drug users who have HIV are coinfected
28

with hepatitis C. Currently, injection drug users account for 60% of the persons
with newly acquired cases of HCV infection in the United States, as well as 22%
of AIDS cases in men and 42% of AIDS cases in women. Therefore, coinfection
with HIV and HCV will be an increasing problem in the coming years.
As the life expectancy of patients with HIV improves, the clinical impact
of HCV as a comorbid condition may be increasingly noticed. Patients with HIV
need to be evaluated for HCV infection, and HCV should be defined as an
opportunistic infection in patients with HIV.

2) Cytomegalovirus
CMV, a beta-herpesvirus, is the major cause of non-Epstein-Barr virus
infectious mononucleosis in the general population and an important pathogen in
immunocompromised hosts, including patients with AIDS, neonates, and
transplant recipients. The risk of exposure to CMV increases with age, and
serologic evidence of prior infection can be detected in approximately 60% of the
general adult population in the United States. Asymptomatic excretion of CMV in
saliva, respiratory secretions, urine, and semen is common and explains the
increasing risk of exposure over time. As with other herpesviruses, CMV remains
latent in the infected host throughout life and rarely reactivates to cause clinical
illness except in immunocompromised individuals.
In patients with AIDS, progressive loss of immune function, and, in particular,
loss of cell-mediated immunity, permits CMV reactivation and replication to
begin; asymptomatic excretion of CMV in urine can be detected in approximately
50% of HIV-infected individuals with a CD4 lymphocyte count <100 cells/L.
Cell-to-cell transmission of CMV results in tissue necrosis in association with
nonspecific inflammation. Transient episodes of CMV viremia can also occur.
Although the clinical significance of viremia is uncertain, such episodes probably
result in dissemination of CMV to other organs (eg, the retina), thereby setting the
stage for subsequent end-organ disease.
29


3) Malnutrition

Malnutrition is a common complication of human immunodeficiency virus
(HIV) infection and plays a significant and independent role in its morbidity and
mortality. Malnutrition was one of the earliest complications of acquired
immunodeficiency syndrome (AIDS) to be recognized. Unexplained weight loss
is one of the most common initial AIDS-defining diagnoses to be reported to
public health authorities.
Malnutrition associated with HIV infection has far-reaching ramifications not
only for the patient, but also for the health care system and society in general.
Many patients become too debilitated to work steadily and come to rely on public
or other assistance. Weight loss often is the initiating event in a vicious cycle of
increased fatigue and decreased physical activity, including the ability to prepare
and consume food. The burden of providing custodial services as well as
specialized nutritional support has strained health care resources and confounds
attempts to provide streamlined and cost-efficient health care. Malnutrition also
was found to increase the rate of complications during hospitalization in other
diseases. This generally results in further medical intervention that may include
expensive diagnostic and therapeutic measures. The increase in expenditure adds
to the overall economic burden of providing health care. To this amount must be
added the cost of lost wages and a decreased level of contribution to society by
affected individuals.

4) Tuberculosis
Tuberculosis (TB) and HIV have been closely linked since the emergence of
AIDS. Worldwide, TB is the most common opportunistic infection affecting HIV-
seropositive individuals, and it remains the most common cause of death in
patients with AIDS. HIV infection has contributed to a significant increase in the
worldwide incidence of TB. By producing a progressive decline in cell-mediated
immunity, HIV alters the pathogenesis of TB, greatly increasing the risk of
30

disease from TB in HIV-coinfected individuals and leading to more frequent
extrapulmonary involvement, atypical radiographic manifestations, and
paucibacillary disease, which can impede timely diagnosis. Although HIV-related
TB is both treatable and preventable, incidence continues to climb in developing
nations wherein HIV infection and TB are endemic and resources are limited.
Interactions between HIV and TB medications, overlapping medication toxicities,
and immune reconstitution inflammatory syndrome (IRIS) complicate the
cotreatment of HIV and TB.

5) Toxoplasmosis
Toxoplasmosis is the leading cause of focal central nervous system (CNS)
disease in AIDS. CNS toxoplasmosis in HIV-infected patients is usually a
complication of the late phase of the disease. Typically, lesions are found in the
brain and their effects dominate the clinical presentation. Rarely, intraspinal
lesions need to be considered in the differential diagnosis of myelopathy. The
decision to treat a patient for CNS toxoplasmosis is usually empiric. Primary
therapy is followed by long-term suppressive therapy, which is continued until
antiretroviral therapy can raise CD4+ counts above 200 cells/L. Prognosis is
guarded. Patients may relapse because of noncompliance or increasing dose
requirements.
6) Pneumocystis Carinii Pneumonia
Pneumocystis carinii pneumonia (PCP) is an opportunistic infection that
occurs in immunosuppressed populations, primarily patients with advanced
human immunodeficiency virus infection. The classic presentation of
nonproductive cough, shortness of breath, fever, bilateral interstitial infiltrates and
hypoxemia does not always appear. Diagnostic methods of choice include sputum
induction and bronchoalveolar lavage. The drug of choice for treatment and
prophylaxis is trimethoprim-sulfamethoxazole, but alternatives are often needed
because of adverse effects or, less commonly, treatment failure. Adjunctive
corticosteroid therapy improves survival in moderate to severe cases.
31

Complications such as pneumothorax and respiratory failure portend poorer
survival. Prophylaxis dramatically lowers the risk of disease in susceptible
populations. Although PCP has declined in incidence in the developed world as a
result of prophylaxis and effective antiretroviral therapy, its diagnosis and
treatment remain challenging.

2.2.11. Prognosis
Although HIV infection is usually deadly in children, especially in
developing countries, the development of new antiretroviral drugs is promising.
The lack of access to antiretroviral agents by children in developing countries is
of particular concern.
The nutritional status of the child and the diligence with which viral
replication is controlled are paramount in determining the outcome of most
children with HIV disease. Aggressive treatment of opportunistic infections
prevents the more deleterious effects of secondary disease from progressing and
further weakening the patient. The social setting and the stressors to which
children are exposed have also been linked to the progression of the disease.
Hematologic disturbances, such as anemia, thrombocytopenia, and
neutropenia, increase the risk of complications and death. Resolution of anemia
improves the prognosis, and treatment of anemia with erythropoietin improves
survival. Neutropenia significantly increases the risk of bacterial infection, and
treatment of neutropenia with granulocyte colony-stimulating factor substantially
decreases the risk of bacteremia and death.
Infection with Mycobacteriumavium complex (MAC) hastens death,
especially in patients with coexisting anemia (defined as a hematocrit < 25%).
The following factors are associated with rapidly progressive disease in
infants:
32

Advanced maternal disease
High maternal viral load
Low maternal CD4
+
count
Prematurity
In utero transmission
High viral load in the first 2 months of life
Lack of neutralizing antibodies
Presence of p24 antigen
AIDS-defining illnesses
Early cytomegalovirus (CMV) infection
Early neurologic disease
Failure to thrive
Early-onset diarrhea
Each logarithmic decrease in the viral load after the start of therapy decreases
the risk of progression by 54%.
Baseline CD4
+
T-lymphocyte percentage and associated intermediate-term
risk of death in HIV-infected children is as follows

:
< 5%: 97%
5-9%: 76%
10-14%: 43%
15-19%: 44%
20-24%: 25%
25-29%: 31%
30-34%: 10%
35%: 33%
Baseline HIV RNA copy number (copies/mL) and associated intermediate-
term risk for death in HIV-infected children is as follows:
Undetectable ( 4,000) : 24%
33

4,001-50,000 : 28%
50,001- 100,000 : 15%
100,001- 500,000 : 40%
500,001-1,000,00 : 40%
1,000,000 : 71%
The natural progression of vertically acquired HIV infection appears to have a
trimodal distribution. Approximately 15% of children have rapidly progressive
disease, and the remainder has either a chronic progressive course or an infection
pattern typical of that observed in adults. Mean survival is about 10 years.
In resource-poor nations, the progression to death is accelerated. In some
instances, close to 45-90% of HIV-infected children died by the age of 3 years.
However, among children and adolescents, the start of combination therapy
including protease inhibitors reduces the intermediate-term risk of death by an
estimated 67%. Also, host genetics play an important role in HIV-1related
disease progression and neurologic impairment
Combination antiretroviral treatment, available in resources settings since
1996, has forestalled disease progression for over 15 years in many individuals.
The full duration of the favorable outcome of therapy is not yet defined, and it is
not known whether adverse effects from the medications will affect mortality or
limit their use. Plasma viremia and age adjusted CD4 lymphocyte counts are used
to assess the risk of progression and response to antiretroviral treatment. With the
introduction of HAART, mortality rates for HIV infected children in the United
States declined 80% between 1994 and 1999. Many children, infected from birth,
are entering adolescence and young adulthood.
With recognition of the longer survival time in most infected children, this
disease is now approached as a chronic, rather than acute terminal, illness. The
complexity of antiretroviral drug therapy requires care from a provider with HIV
expertise. Primary case physicians are encouraged to participate in the care of
34

HIV infected children in collaboration with centers staffed by personnel with
expertise in pediatric HIV issues.











CHAPTER IV
DISCUSSION AND SUMMARY










35

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