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HIV INFECTION IN CHILDREN

Presentators : Raja Hasayangan Siregar

Rizki Ananda Lubis (090100011)

Day, Date : Wednesday, 24ndApril 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 intervention1. 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 inchildren 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 goodprognosis.

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 CentralAsia 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.2The 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.3

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.4

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 lymphnodes.

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-infectedchildren, 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

(


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Unexplained anaemia (


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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


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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


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Table 2.6 Indications for initiation of antiretroviral therapy in children infected

with human immunodeficiency virus (HIV)

Age Criteria Reccomendation


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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


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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


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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


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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.


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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:


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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%


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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


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HIV infected children in collaboration with centers staffed by personnel with

expertise in pediatric HIV issues.

CHAPTER IV

DISCUSSION AND SUMMARY


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1. World Health Organization. Strategic Vision. World Health Organization.

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UNAIDS Report on the Global AIDS Epidemic 2010. Available

athttp://www.unaids.org/globalreport/Global_report.htm.

3. Garrib A, Jaffar S, Knight S, Bradshaw D, Bennish ML. Rates and causes

of child mortality in an area of high HIV prevalence in rural South

Africa. Trop Med Int Health. Dec 2006;11(12):1841-8.

4.

Preidis GA, McCollum ED, Mwansambo C, Kazembe PN, Schutze GE,

Kline MW. Pneumonia and malnutrition are highly predictive of mortality

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0/abstract

7. Greenfield, R.A. Pediatric HIV Infection. Available at:

http://emedicine.medscape.com/article/965086-overview

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Soedarmo SSP, Garna H, Hardinegoro SRS, Satari HI. Varisela. Dalam :

Buku Ajar Infeksi dan Pediatri Tropis. Edisi ke-2. Jakarta: Badan Penerbit

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