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Acute Bronchitis

2008-09-13T19:47:00.002+08:00

Acute Bronchitis

Susan Davids, MD, MPH and Ralph M. Schapira, MD in Rakel & Bope: Conn's Current Therapy 2008, 60th ed.

Acute bronchitis is one of the most common diagnoses made by primary care physicians in the United States and accounts for nearly 10 million office visits per year. Acute bronchitis is a transient, self-limited inflammatory process of the upper respiratory tract, specifically the trachea and bronchi. Antibiotics are overprescribed to patients with acute bronchitis; this practice has raised significant concern related to the worldwide rise of antibiotic resistance, which is viewed as one of the world's most pressing public health problems.

Acute bronchitis manifests as an acute respiratory illness of less than 3 weeks' duration, with or without sputum production. Acute bronchitis is a clinical diagnosis and must be distinguished from other respiratory diseases, such as pneumonia, acute exacerbation of chronic bronchitis (episode of worsening of symptoms and expiratory airflow obstruction in patients with chronic obstructive pulmonary disease), and the onset of asthma. Most cases of acute bronchitis occur in the fall and winter. The etiology of acute bronchitis is infectious, and viruses appear to be the cause of most cases. Influenzas A and B are the most common viruses isolated, although a wide variety of infectious agents have been identified, such as adenovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, coxsackievirus, Mycoplasma pneumoniae, Bordetella pertussis, and Chlamydia pneumoniae.

Diagnosis of acute bronchitis is based on findings of a prominent cough that may be accompanied by wheezing and sputum production. Most patients are otherwise healthy and without preexisting respiratory disease. Nonspecific constitutional symptoms may also be part of acute bronchitis. Appropriate management of acute bronchitis is essential because it is one of the most common illnesses that present to physicians in the outpatient setting. Antibiotics are often prescribed unnecessarily for acute bronchitis and other respiratory tract illnesses; these prescriptions may potentially lead to adverse events (i.e., allergic reactions and gastrointestinal side effects) and bacterial resistance. Other medications, such as inhaled bronchodilators and antitussives, are often prescribed for acute bronchitis despite questionable evidence to support their routine use.

Pathophysiology of acute bronchitis involves an acute inflammatory response involving the mucosa of the trachea and bronchi, resulting in injury to the respiratory tract epithelium. Sputum production is increased and bronchoconstriction (potentially resulting in airflow obstruction and wheezing) can occur. Positron emission tomography (PET) of a patient with acute bronchitis confirms that the primary inflammatory changes occur in the trachea and bronchi and not the remainder of the lower respiratory track.

CURRENT DIAGNOSIS

1. Normal healthy adult with cough

2. Predominance of cough

3. Lasts 1 to 3 weeks

4. With or without sputum

5. Can be accompanied by other respiratory and constitutional symptoms

6. Absence of abnormal vital signs and physical exam suggesting pneumonia,particularly

Heart rate >100 beats per minute

Respiratory rate >24 breaths per minute

Temperature >100.4°F (38°C)

Lung findings suggest a consolidation process

Diagnosis

Cough, phlegm (which may be purulent as both bacteria and viruses can cause purulent sputum), and wheezing help differentiate acute bronchitis from upper respiratory infections such as pharyngitis and sinusitis. Acute bronchitis must be differentiated from acute bacterial pneumonia. The absence of abnormalities in vital signs (heart rate >100 bpm, respiratory rate >24 breath/min, oral temperature >100.4°F [38°C] and physical examination of the chest) supports the diagnosis of acute bronchitis and makes the need for chest radiography unnecessary in most cases. The treatment and outcome of acute bronchitis and pneumonia are very different; a chest radiograph should always be obtained if there is uncertainty about the diagnosis. Chest radiography will demonstrate no lung infiltrates in a patient with acute bronchitis. In contrast, lung infiltrates are present in pneumonia. Pertussis or whooping cough should be considered in adults with cough in the setting of what appears to be an upper respiratory infection, even in those previously immunized. Typically, the cough of pertussis, unlike acute bronchitis, lasts for longer than 3 weeks. Other respiratory diseases, such as previously undiagnosed asthma, can also mimic acute bronchitis, although several features differentiate asthma from acute bronchitis (see Section 12). Rapid testing to diagnose influenza viruses A and B (the most common causes of acute bronchitis) as a cause of acute bronchitis should be considered given the availability of effective treatment if initiated in the first 48 hours.

Treatment

ANTIBIOTICS, INHALED BRONCHODILATORS, AND ANTITUSSIVES

Existing evidence does not support the routine use of antibiotics for uncomplicated cases of acute bronchitis. Although most cases of acute bronchitis are caused by viral infections, upwards of 60% of patients are prescribed antibiotic therapy, which is contributing to the rise of bacterial resistance to commonly used antibiotics. Meta-analyses examining the effectiveness of antibiotic therapy in patients without underlying lung disease suggest no consistent effect of antibiotics on the severity or duration of acute bronchitis. A recent study evaluated children and patients with colored sputum and found that they also did not benefit from antibiotics. This study also found that compared to other populations, the elderly were less likely to benefit from antibiotics. Smokers with acute bronchitis are even more likely to be prescribed antibiotics.

Their response to antibiotics was either equal to or worse than that of nonsmokers.

CURRENT THERAPY

Antibiotics not routinely recommended

If influenza is highly probable and patient is presenting within the first 48 hours, consider treatment with :

a. Oseltamivir (Tamiflu) 75 mg PO bid with food for 5 days (influenza A/B)

b. Zanamivir (Relenza) 10 mg bid by inhalation for 5 days (influenza A/B) [*]

c. Amantadine (Symmetrel) 100 mg bid or 200 mg once daily for 5 days (influenza A) [*]

d. Rimantadine (Flumadine) 100 mg bid for 5 days (influenza A)

In patients with evidence of bronchial hyperresponsiveness, consider treatment with

a. β₂-agonists for 1 to 2 weeks

b. Antitussives in those with cough for 2 to 3 weeks

c. Antipyretics and analgesics as needed

d. Smoking cessation

Education: cough likely to last 3 weeks or more.

' Due to emergence of antiviral resistance, use of these agents has been discouraged by the CDC.

One possible reason for overuse of antibiotics is the concern by physicians about patient satisfaction. Studies show that patients presenting to the doctor expecting antibiotics were more likely to be prescribed antibiotics; studies also suggest that satisfaction is more related to appropriate patient education than to receiving antibiotics. Patient education should include information regarding the duration of symptoms associated with acute bronchitis. It was found that patients presented on average after 9 days of cough and that the cough persisted for an additional 12 days after the physician visit. This information can impart a realistic expectation of illness duration to the patient.

If influenza is highly suspected and the patient presents within 48 hours of the onset of symptoms, rapid diagnostic testing and treatment should be considered. Both amantadine (Symmetrel) and rimantadine (Flumadine) are effective for influenza A, and neuraminidase inhibitors, inhaled zanamivir (Relenza), and oral oseltamivir (Tamiflu) are effective for influenzas A and B. If these medications are initiated within the first 48 hours of symptoms (and ideally within 30 hours), the duration of illness can be shortened.

The evidence supporting the use of inhaled bronchodilators for the treatment of the symptoms has been variable. Two small trials reported a shorter duration of cough with the use of inhaled ß-agonists; another study reported benefit in those with evidence of bronchial hyperresponsiveness. Current recommendations support the use of ß-agonists only in patients with evidence of bronchial hyperresponsiveness (wheezing or spirometry demonstrating a forced expiration volume in 1 second [FEV₁] <80%>

Antitussive agents have not been shown to improve the acute or early cough but did show some improvements in cough lasting longer than 3 weeks. The current recommendations are to use antitussives, namely dextromethorphan (Benylin) or codeine, in patients with cough of 2 to 3 weeks' duration.

Acute uncomplicated bronchitis is most often a viral illness in which antibiotics are not routinely indicated. Patients presenting with an acute respiratory illness, who are younger than 65 years old without existing pulmonary disease or other significant comorbid illness, should have a thorough physical examination, including vital signs. If the vital signs are normal and physical examination of the chest is clear, pneumonia can most likely be ruled out. In patients who present within 48 hours of onset of symptoms, influenza should be considered as effective therapy is available for acute bronchitis caused by influenzas A or B. Otherwise, the evidence for treatment with antibiotics does not support their routine use. Bronchodilators should be considered in those with evidence of bronchial hyperresponsiveness; cough suppressants should be considered in those with 2 to 3 weeks of cough. Patient education is an integral part of the treatment, and patients should receive information that provides realistic expectations regarding the duration of cough.

Acne Vulgaris

2008-09-11T22:19:00.007+08:00

Acne ulgaris

Major points

Most prevalent skin disorder in pediatrics

1. Affects 40% of children aged 8–10 years
2. Affects 85% of adolescents aged 15–17 years

Lesion types:

1. Comedones: obstructive lesions
a. Microcomedone: microscopic plugging of the hair follicle that is the precursor lesion to
acne vulgaris
b. Open comedone (blackhead): plugging at the follicular opening; cellular plug of stratum
corneum with oxidized melanin within the follicle (Figure 1)

Figure 1 Comedonal acne - on forehead with open and closed comedones

c. Closed comedone (whitehead): plugging of the pilosebaceous unit just below the
follicular opening with cystic swelling of the duct; filled with cellular debris
2. Inflamatory lesions: papules, pustules, cysts, sinus tracts (Figures 2–4)
3. Scars: depressed, pitted, macular, papular, hypertrophic, keloidal

Acne is one of the earliest stages of adrenarche
Lesion type often correlates with pubertal stage
1. Comedonal acne is predominant type in prepubertal children
2. Inflammatory acne is more prevalent in adolescents

Develops in areas with high numbers of pilosebaceous units: face, chest, back
Increased severity often predicted by earlier onset and positive family history of scarring acne

Figure 2 Papulopustular acne - numerous erythematous papules and pustules on the face

Figure 3 Cystic acne on the chest with erythematous nodules, crusts and scarring

Figure 4 Inflammatory acne with comedones, erythematous papules and nodules on the back of a teenager

Pathogenesis

Acne development is a complex process that involves four main contributing factors :
1. Abnormal keratinization and obstruction of the pilosebaceous unit
a. Initial lesion is a microcomedone; caused by obstruction of the follicular opening with
the accumulation of cellular debris
b. Obstruction is due to abnormal keratinization of the cells lining the follicle with delayed
shedding and increased cohesiveness
2. Hormonal stimulation and increased sebum production
a. Increased secretion and accumulation of sebum within the follicle which is stimulated
by increased adrenal and gonadal androgens that occur with adrenache
b. Poly cystic ovary syndrome, a heterogeneous disorder with altered gonadotropin
secretion, hyperandrogenism (acne, hirsutism and virilization), chronic anovulation,
obesity and insulin resistance
3. Bacterial overgrowth
a. Propionibacterium acnes overgrows within the dilated follicle
b. Bacterial lipases convert accumulated sebum triglycerides into free fatty acids that
cause inflammation
c. P. acnes also releases other proteolytic enzymes and chemotactic factors that further
stimulate inflammation and recruitment of polymorphonuclear cells (PMNs)
4. Inflammatory reaction
a. Inflammatory cells including PMNs are recruited to the area
b. Ingestion of bacteria by PMNs causes release of hydrolytic enzymes that causes
rupture of the follicular wall
c. This leads to intense inflammation and a surrounding foreign body reaction

Diagnosis

Clinical findings

Differential diagnosis

Drug-induced acne
Chemical-induced acne
Rosacea
Gram-negative folliculitis
Pityrosporum folliculitis

Treatment

Topical retinoids: important for normalizing keratinization (e.g. tretinoin, adapalene)
Topical keratolytics: salicylic acid, azelaic acid
Topical benzoyl peroxide preparations
Topical antibiotics: clindamycin, erythromycin
Systemic antibiotics for inflammatory lesions
1. Doxycycline, tetracycline and minocycline most commonly used in those >9 years of age
Systemic retinoids for severe cystic acne or early scarring
Oral contraceptives

Prognosis

Can have significant impact on social interactions and self-esteem and can lead to depression in severe cases
May produce significant scarring in inflammatory and cystic lesions
Can rarely be associated with an underlying endocrine disorder

References
Cunliffe WJ, Holand DB, Clark SM, Stable GI. Comedogenesis: some new aetiological, clinical and therapeutic strategies. Br J Dermatol 2000; 142: 1084–91
Harper JC, Thiboutot DM. Pathogenesis of acne: recent research advances. Adv Dermatol 2003; 19: 1–10
Lee DJ, VanDyke GS, Kim J. Update on pathogenesis and treatment of acne. Curr Opin Pediatr 2003; 15: 405–10
Leyden JJ. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol 2003; 49: S200–10
Lucky AW, Biro FM, Simbartl LA, et al. Predictors of severity of acne vulgaris in young adolescent girls: results of a five-year longitudinal study. J Pediatr 1997; 130: 30–9
Weiss JS. Current options for topical treatment of acne vulgaris. Pediatr Dermatol 1997; 14: 480–8

Bullous Pemphigoid

2008-09-11T19:00:00.003+08:00

Bullous Pemphigoid

Major points

Large, tense blisters arising on normal or erythematous skin
Mucous membrane involvement in 10–35%
Sites of predilection: lower abdomen, inner thighs, flexor forearms or generalized
Bullae may have clear or hemorrhagic fluid

(Figures 1 and 2)

Figure 1. Bullous pemphigoid - large bullae on erythematous patches

Figure 2. Pemphigoid gestationis - in a young pregnant woman. Her child was unaffected

Erosions tend to re-epithelialize quickly
Nikolsky sign is negative
New vesicles may form at the edge of old blisters
Blisters do not tend to scar but may be hyperpigmented
Mild to moderate pruritus
Early lesions tend to look urticarial
Rare in childhood

Pathogenesis

Bullous pemphigoid (BP) antigens are proteins in the hemidesmosomes (HDs). Autoantibody binds both inside the cell to plaques of HDs and outside cells to the extracellular section of HDs
BP antibodies are directed against both BPAg-1 (230 kDa) component and also BPAg-2 (180kDa) (also called type XVII collagen)

BP IgG can activate complement by the classical pathway causing leukocyte adherence to the basement membrane, degranulation of polymorphonuclear leukocytes and subsequent dermal–epidermal separation

Diagnosis

Histology: Subepidermal blister without necrosis, and superficial dermal infiltrate with lymphocytes, histiocytes and eosinophils
DIF: linear pattern of C3 and IgG at BMZ

Indirect immunoflourescence: 70–80% of patients will have circulating IgG which binds to stratified squamous epithelium; titers do not correlate with disease extent or activity ~50% have elevated IgE, and sometimes eosinophilia, which correlates with pruritus

Differential diagnosis

Bullous insect bite reactions
Bullous impetigo
Bullous erythema multiforme
Chronic bullous disease of childhood

Treatment

Prednisone 1–2mg/kg per day until activity is suppressed. Once under control, steroids should be tapered to avoid side-effects
Steroid-sparing agents can be used as an adjunct: cyclophosphamide, azathioprine, cyclosporine, methotrexate, or gold
Localized BP can be treated with high-potency topical steroids
Some patients respond to sulfones, tetracycline, or nicotinamide

Prognosis
BP may be self-limited and can last several months to many years
Prognosis is good. In adults, half of treated patients go into remission in 2.5–6 years

Venomous Snakebite

2008-09-10T13:26:00.005+08:00

Venomous Snakebite

Epidemiology

Venomous snakes (Fig. 1) of the world belong to the families Viperidae (subfamily Viperinae: Old World vipers; subfamily Crotalinae: New World and Asian pit vipers), Elapidae (including cobras, kraits, coral snakes, and all Australian venomous snakes), Hydrophiidae (sea snakes), Atractaspididae (burrowing asps), and Colubridae (a large family, of which most species are nonvenomous and only a few are dangerously toxic to humans). Bite rates are highest in temperate and tropical regions where the population subsists by manual agriculture. Estimates indicate >5 million bites annually by venomous snakes worldwide, with >125,000 deaths.

Figure 1. Types of highly venomous snakes. (A).The Viperidae, (B). The Elapidae, (C). Hydrophiidae (D). Atractaspididae

Snake Anatomy/Identification

The typical snake-venom apparatus consists of bilateral venom glands located below and behind the eye and connected by ducts to hollow, anterior maxillary teeth. In viperids (vipers and pit vipers), these teeth are long mobile fangs that retract against the roof of the mouth when the animal is at rest. In elapids and sea snakes, the fangs are smaller and are relatively fixed in an erect position. In ~20% of pit viper bites and higher percentages of other snakebites (e.g., up to 75% for sea snakes), no venom is released ("dry" bites). Significant envenomation probably occurs in ~50% of all venomous snakebites.

Differentiation of venomous from nonvenomous snake species can be difficult. Viperids are characterized by somewhat triangular heads (a feature shared with many harmless snakes); elliptical pupils (also seen in some nonvenomous snakes, such as boas and pythons); enlarged maxillary fangs; and, in pit vipers, paired heat-sensing pits (foveal organs) on each side of the head. The New World rattlesnakes generally have a series of interlocking keratin plates (the rattle) on the tip of the tail; the rattle is used to warn potentially threatening intruders. Color pattern is notoriously misleading in identifying most venomous snakes. Many harmless snakes have color patterns that closely mimic venomous snakes found in the same region.

Venoms and Clinical Manifestations

Snake venoms are complex mixtures of enzymes, low-molecular-weight polypeptides, glycoproteins, and metal ions. Among the deleterious components are hemorrhagins that promote vascular leakage and cause both local and systemic bleeding. Proteolytic enzymes cause local tissue necrosis, affect the coagulation pathway at various steps, and impair organ function. Myocardial depressant factors reduce cardiac output, and neurotoxins act either pre- or postsynaptically to inhibit peripheral nerve impulses. Most snake venoms have multisystem effects in their victims.

Envenomations by most viperids and some elapids with necrotizing venoms typically cause progressive local swelling, pain, ecchymosis (Fig. 2), and (over a period of hours or days) hemorrhagic bullae and serum-filled vesicles. In serious bites, tissue loss can be significant (Fig. 3). Systemic findings can include changes in taste, mouth numbness, muscle fasciculations, tachycardia or bradycardia, hypotension, pulmonary edema, hemorrhage (from essentially any anatomic site), and renal dysfunction. Envenomations by neurotoxic elapids such as kraits (Bungarus spp.), many Australian elapids [e.g., death adders (Atractaspis spp.) and tiger snakes (Notechis spp.)], some cobras (Naja spp.), and some viperids [e.g., the South American rattlesnake (Crotalus durissus) and some Indian Russell's vipers (Daboia russelii)] cause neurologic dysfunction. Early findings may consist of cranial nerve weakness (e.g., manifested by ptosis) and altered mental status. Severe poisoning may result in paralysis, including the muscles of respiration, and lead to death due to respiratory failure and aspiration. After elapid bites, the time of onset of venom intoxication varies from minutes to hours depending on the species involved, the anatomic location of the bite, and the amount of venom injected. Sea snake envenomation usually causes local pain (variable), myalgias, rhabdomyolysis, and neurotoxicity; these manifestations are occasionally delayed for hours.

Figure 2. Northern Pacific rattlesnake (Crotalus oreganus oreganus) envenomations. Top: Moderately severe envenomation. Note edema and early ecchymosis 2 h after a bite to the finger. Bottom: Severe envenomation. Note extensive ecchymosis 5 days after a bite to the ankle.

Figure3. Early stages of severe, full-thickness necrosis 5 days after a Russell's viper (Daboia russelii) bite in southwestern India

Treatment

Field Management

The most important aspect of prehospital care of a victim bitten by a venomous snake is rapid delivery to a medical facility equipped to provide supportive care (airway, breathing, and circulation) and antivenom administration. Most first aid recommendations made in the past are of little benefit, and some can actually worsen outcome. It is reasonable to apply a splint to the bitten extremity in order to lessen bleeding and discomfort and, if possible, to keep the extremity at approximately heart level. In developing regions, indigenous people should be encouraged to seek care quickly at health care facilities equipped with antivenoms as opposed to consulting traditional healers.

Although mechanical suction has been recommended in the field management of venomous snakebite for many years, there is now evidence that this intervention is of no benefit and can actually be deleterious in terms of local tissue damage.

Techniques or devices used for centuries in an effort to limit venom spread remain controversial. Lympho-occlusive bandages or tourniquets may limit spread only at the cost of greater local tissue damage, particularly with necrotic venoms. Because tourniquets lead to higher rates of amputation and loss of function, they absolutely should not be used. Elapid venoms that are primarily neurotoxic and have no significant local tissue effects may be localized by pressure-immobilization, in which the entire limb is immediately wrapped with a bandage (e.g., crepe or elastic) and then splinted. The wrap pressure must reach ~40–70 mmHg to be effective. Furthermore, if more than a few minutes from medical care, the victim must be carried out from the scene of the bite. Otherwise, muscular pumping will promote venom dispersal, even in bites to the upper extremities. In short, pressure-immobilization should be used only in cases where the offending snake is reliably identified and has a primarily neurotoxic venom, the rescuer is skilled in pressure-wrap application, and the victim can be carried to medical care—an uncommon combination of conditions. Besides tourniquets, other forbidden measures include incising or cooling the bite site, giving the victim alcoholic beverages, and applying electric shocks. The best first aid advice, as coined by Dr. Ian Simpson of the World Health Organization's Snakebite Treatment Group, is to "do it 'RIGHT'": reassure the victim, immobilize the extremity, get to the hospital, and inform the physician of telltale symptoms and signs.

Hospital Management

In the hospital, the victim should be closely monitored (vital signs, cardiac rhythm, oxygen saturation, urine output) while a history is quickly obtained and a rapid, thorough physical examination is performed. Victims of neurotoxic envenomation should be watched carefully for evidence of difficulty swallowing or respiratory insufficiency, which should prompt definitive securing of the airway by endotracheal intubation. To provide objective evidence of the progression of envenomation, the level of swelling in a bitten extremity should be marked and limb circumferences measured in several locations every 15 min until swelling has stabilized. Large-bore IV access in unaffected extremities should be established. Early hypotension is due to pooling of blood in the pulmonary and splanchnic vascular beds. Later, hemolysis and loss of intravascular volume into soft tissues may play important roles. Fluid resuscitation with isotonic saline should be initiated for clinical shock. If the blood pressure response to administration of crystalloid (20–40 mL/kg) is inadequate, a trial of 5% albumin (10–20 mL/kg) is prudent. If tissue perfusion fails to respond to volume resuscitation and antivenom infusion (see below), vasopressors (e.g., dopamine) can be added. Invasive hemodynamic monitoring (central venous and/or pulmonary arterial pressures) can be helpful in such cases, although obtaining access is risky if coagulopathy has developed.

Blood should be drawn for typing and cross-matching and for laboratory evaluation as soon as possible. Important studies include a complete blood count (to evaluate degree of hemorrhage or hemolysis and effects on platelet count), studies of renal and hepatic function, coagulation studies (to identify consumptive coagulopathy), and testing of urine for blood or myoglobin. In developing regions, the 20-min whole-blood clotting test (WBCT) can be used to diagnose coagulopathy reliably. A few milliliters of fresh blood are placed in a new, plain glass receptacle (e.g., test tube) and left undisturbed for 20 min. The tube is then tipped once to 45° to determine whether a clot has formed. If not, coagulopathy is diagnosed. In severe envenomations or with significant comorbidity, arterial blood gas studies, electrocardiography, and chest radiography may be helpful. Any arterial puncture in the setting of coagulopathy, however, requires great caution and must be performed at an anatomic site amenable to direct-pressure tamponade. After antivenom therapy (see below), laboratory values should be rechecked every 6 h until clinical stability is achieved.

The key to management of venomous snakebite is the administration of specific antivenom. Circulating venom components bind quickly with heterologous antibodies produced in animals immunized with the venom in question (or a very closely related venom). Antivenoms may be monospecific (for a particular snake species) or polyspecific (covering several medically important species in the region) but rarely offer cross-protection against snake species other than those used in their production unless the species are known to have homologous venoms. In the United States, assistance in finding antivenom can be obtained 24 h a day from regional poison control centers.

Indications for antivenom administration in victims of viperid bites include any evidence of systemic envenomation (systemic symptoms or signs; laboratory abnormalities) and (possibly) significant, progressive local findings (e.g., soft tissue swelling crossing a joint or involving more than half the bitten limb in the absence of a tourniquet). Care must be used in determining the significance of isolated soft-tissue swelling as, in many countries, the saliva of some relatively harmless snakes causes mild edema at the bite site. In such bites, antivenoms are unhelpful and unnecessary.

In the developing world (e.g., much of Asia and Africa), elapid bites are generally treated similarly to viperid bites. Systemic symptoms such as ptosis, other manifestations of cranial nerve impairment, or respiratory compromise constitute grounds for antivenom administration. Decisions about antivenom administration to victims with isolated local signs or symptoms are based on the criteria listed above for viperid bites.

Production of the only antivenom currently available in the United States for coral snake bites has been discontinued, and remaining stocks will be exhausted or will expire shortly. Until a suitable substitute is produced or imported, physicians caring for victims of Micrurus bites may have to rely on sound supportive care, especially airway management and respiratory support.

The package insert for the selected antivenom can be consulted regarding species covered, method of administration, starting dose, and need (if any) for re-dosing. The information in antivenom package inserts, however, is not always accurate and reliable. Whenever possible, it is advisable for treating physicians to seek advice from experts in snakebite management regarding indications for and dosing of antivenom. For viperid bites, antivenom administration should generally be continued as needed until the victim shows definite improvement (e.g., stabilized vital signs, reduced pain, restored coagulation). Neurotoxicity from elapid bites may be harder to reverse with antivenom. Once neurotoxicity is established and endotracheal intubation is required, further doses of antivenom are unlikely to be beneficial. In such cases, the victim must be maintained on mechanical ventilation until recovery occurs, which may take days to weeks.

The newest available antivenom in the United States (CroFab; Fougera, Melville, NY) is an ovine, Fab fragment antivenom that covers systemic venom effects of all North American pit viper species and carries a low risk of allergic sequelae. Table 1 compares the two antivenoms recently available for the treatment of pit viper bites in the United States. The manufacturer of Antivenin (Crotalidae) Polyvalent has recently discontinued its production, leaving CroFab as the current drug of choice for the management of indigenous pit viper envenomations in the United States. Use of any heterologous serum product carries a risk of anaphylactoid reactions and delayed-hypersensitivity reactions (serum sickness). Skin testing for potential allergy is insensitive and nonspecific and should be omitted. Worldwide, the quality and availability of antivenoms are highly variable. In many developing countries, antivenom resources are scarce, contributing to high morbidity and mortality rates in these regions. The rates of acute anaphylactoid reactions to some of these products exceed 50%. If the risk of allergic reaction is significant, pretreatment with appropriate loading doses of IV antihistamines (e.g., diphenhydramine, 1 mg/kg to a maximum of 100 mg; and cimetidine, 5–10 mg/kg to a maximum of 300 mg) may be considered. In some regions, a prophylactic SC or IM dose of epinephrine is given in an effort to reduce the risk of reaction. Further research is necessary to determine whether any pretreatment measures are truly beneficial. Modest expansion of the patient's intravascular volume with crystalloids could blunt an acute adverse reaction.

Table 1 Comparison of Antivenoms Recently Available for Treatment of Pit Viper Bites in the United States

	Antivenin (Crotalidae) Polyvalent^a	CroFab^b
Available since	1954	2000
Origin	Equine	Ovine
Snakes used in manufacture	Crotalus adamanteus	C. adamanteus
	C. atrox	C. atrox
	C. durissus terrificus	C. scutulatus
	Bothrops atrox	Agkistrodon piscivorus
Snakes covered	All North, Central, and South American and some Asian pit vipers	All North American pit vipers (and possibly other Latin American pit vipers)
Contains	IgG, equine albumin	Fab fragments
Skin testing recommended by manufacturer	Yes	No
Pretreatment with antihistamines recommended	Yes	No
Dosing (for North American pit viper bites only)^c
Dry bite	None	None
Mild	0 or 5 vials	4 vials
Moderate	10 vials	4–6 vials
Severe	15–20 vials	6 vials
Repeat dosing	As needed	Repeat starting dose if patient fails to stabilize. After stabilization, give 2 vials q6h for 3 more doses. (Alternatively, re-dose on an as-needed basis with close observation for recurrence of abnormalities.)
Volume of diluent	1000 mL^d	250 mL
Administer over	2 h	1 h
Incidence of anaphylactic/-oid reaction	23–56%^e	14%^f
Incidence of delayed serum sickness	18–86%^g	3%

^aWyeth-Ayerst Laboratories, Philadelphia, PA.

^bFougera, Melville, NY.

^cDegrees of envenomation: mild = progressive local findings (no systemic findings and normal laboratory tests); moderate = local findings plus either mild systemic findings or mild laboratory abnormalities; and severe = local findings plus either severe systemic findings or severe laboratory abnormalities.

^dReduce for children and for patients with congestive heart failure.

^eSome reactions have been severe, and some have been fatal.

^fTo date, all reactions have been relatively mild.

^gIncidence is higher with larger doses.

Pretreatment is not recommended by the manufacturer of CroFab. Epinephrine should, however, always be immediately available, and the antivenom dose to be administered should be diluted in an appropriate volume of crystalloid according to the package insert. Antivenom should be given only by the IV route, and the infusion should be started slowly, with the physician at the bedside during the initial period to intervene immediately at the first signs of any acute reaction. The rate of infusion can be increased gradually in the absence of a reaction until the full starting dose has been administered (over a total period of ~1 h). Further antivenom may be necessary if the patient's clinical condition fails to stabilize or worsens. After stabilization, additional doses of CroFab are often recommended as the small-molecular-weight Fab fragments are rapidly cleared from the circulation. Larger, whole IgG or F(ab)2 antivenoms have longer half-lives that eliminate the need for re-dosing after initial stabilization unless definitive symptoms of envenomation reappear.

If the patient develops an acute reaction to antivenom, the infusion should be temporarily stopped and the reaction immediately treated with IM epinephrine and IV antihistamine and steroids (Chap. 311). If the severity of envenomation warrants additional antivenom, the dose should be further diluted in isotonic saline and restarted as soon as possible. Rarely, in recalcitrant cases, a concomitant IV infusion of epinephrine may be required to hold allergic sequelae at bay while further antivenom is administered. The patient must be very closely monitored, preferably in an intensive care setting, during such therapy.

Blood products are rarely necessary in the management of the envenomated patient. The venoms of many snake species can cause a drop in platelet count or hematocrit and depletion of coagulation factors. Nevertheless, these components usually rebound within hours after administration of adequate antivenom. If the need for blood products is thought to be great (e.g., for a dangerously low platelet count in a hemorrhaging patient), these products still should be given only after adequate antivenom administration to avoid adding fuel to ongoing consumptive coagulopathy.

Rhabdomyolysis and hemolysis should be managed in standard fashion. Victims who develop acute renal failure should be evaluated by a nephrologist and referred for dialysis (peritoneal or hemodialysis) as needed. Such renal failure, usually due to acute tubular necrosis, is frequently reversible. If bilateral cortical necrosis occurs, however, the prognosis for renal recovery is more grim, and long-term dialysis with possible renal transplantation may be necessary.

Acetylcholinesterase inhibitors (e.g., edrophonium and neostigmine) may promote neurologic improvement in patients bitten by snakes with postsynaptic neurotoxins. Victims with objective evidence of neurologic dysfunction after snakebite should receive a trial of acetylcholinesterase inhibitors as outlined in Table 2. If they respond, additional doses of long-acting neostigmine can be continued as needed. Special vigilance is required to prevent aspiration if repetitive dosing of neostigmine is used in an attempt to obviate endotracheal intubation.

Table 2 Use of Acetylcholinesterase Inhibitors in Neurotoxic Snake Envenomation

1. Patients with clear, objective evidence of neurotoxicity after snakebite (e.g., ptosis or inability to maintain upward gaze) should receive a trial of edrophonium (if available) or neostigmine.

a. Pretreat with atropine: 0.6 mg IV (children, 0.02 mg/kg; minimum of 0.1 mg)

b. Follow with:

Edrophonium: 10 mg IV (children, 0.25 mg/kg)

Neostigmine: 1.5–2.0 mg IM (children, 0.025–0.08 mg/kg)

2. If objective improvement is evident at 5 min, continue neostigmine at a dose of 0.5 mg (children, 0.01 mg/kg) every 30 min as needed, with continued administration of atropine by continuous infusion of 0.6 mg over 8 h (children, 0.02 mg/kg over 8 h).

3. Maintain vigilance regarding aspiration risk, and secure the airway with endotracheal intubation as needed.

Care of the bite wound includes application of a dry sterile dressing and splinting of the extremity with padding between the digits. Once the administration of an indicated antivenom has been initiated, the extremity should be elevated above heart level to relieve edema. Tetanus immunization should be updated as appropriate. Prophylactic antibiotics are generally unnecessary after bites by North American snakes, as the incidence of secondary infection is low. Antibiotics can be considered, however, if misguided first-aid efforts have included incisions or mouth suction. In some regions of the world, secondary bacterial infection is more common and the consequences are dire. In these regions, prophylactic antibiotics (e.g., cephalosporins) are commonly used.

Most snake envenomations involve subcutaneous deposition of venom. On occasion, however, venom can be injected more deeply into muscle compartments. If swelling in the bitten extremity raises concern that subfascial muscle edema may be impeding tissue perfusion (muscle-compartment syndrome), intracompartmental pressures (ICPs) should be checked by any minimally invasive technique—e.g., wick catheter or ICP monitor (Stryker Instruments, Kalamazoo, MI). If any ICP is high (>30–40 mmHg), the extremity should be kept elevated while further antivenom is given. A dose of IV mannitol (1 g/kg) can be given in an effort to reduce muscle edema if the patient's hemodynamic status is stable. If, after 1 h of such therapy, the ICP remains elevated, a surgical consultation for possible fasciotomy should be obtained. While evidence from studies of animals suggests that fasciotomy may actually worsen myonecrosis, compartmental decompression is still required to preserve nerve function. Fortunately, the incidence of muscle-compartment syndrome is very low following snakebite.

Wound care in the days after the bite may require careful aseptic debridement of clearly necrotic tissue once coagulation has been restored. Intact serum-filled vesicles or hemorrhagic blebs should be left undisturbed. If ruptured, they should be debrided with sterile technique.

Physical therapy should be started when pain allows in order to return the victim to a functional state. The incidence of long-term loss of function (e.g., reduced range of motion, impaired sensory function) is unclear but is probably quite high (>30%), particularly after viperid bites.

Any patient with signs of venom poisoning should be observed in the hospital for at least 24 h. In North America, a patient with an apparently "dry" viperid bite should be watched for at least 8 h before discharge, as significant toxicity occasionally develops after a delay of several hours. The onset of systemic symptoms is commonly delayed for a number of hours after bites by several of the elapids (including coral snakes), some non–North American viperids [e.g., the hump-nosed pit viper (Hypnale hypnale)], and sea snakes. Patients bitten by these reptiles should be observed in the hospital for at least 24 h. Unstable patients should be admitted to a monitored setting.

At discharge, victims of venomous snakebite should be warned about signs and symptoms of wound infection and serum sickness as well as other potential long-term sequelae, such as pituitary insufficiency in Russell's viper (D. russelii) bites. If the victim had evidence of coagulopathy early on, this abnormality can recur during the first 2–3 weeks after the bite. Such victims should be warned to avoid elective surgery or activities posing a high risk of trauma during this period. Outpatient analgesic treatment and physical therapy should be continued.

In the event of serum sickness (fever, chills, urticaria, myalgias, arthralgias, and possibly renal or neurologic dysfunction developing 1–2 weeks after antivenom administration), the victim should be treated with systemic glucocorticoids (e.g., oral prednisone, 1–2 mg/kg daily) until all findings resolve, at which point the dose is tapered over 1–2 weeks. Oral antihistamines (e.g., diphenhydramine in standard doses) provide additional relief of symptoms.

Morbidity and Mortality

The overall mortality rates for venomous snakebite are low in areas with rapid access to medical care and appropriate antivenoms. In the United States, for example, the mortality rate is <1% for victims who receive antivenom. Eastern and western diamondback rattlesnakes (Crotalus adamanteus and C. atrox, respectively) are responsible for the few snakebite deaths occurring in the United States. Snakes responsible for large numbers of deaths in other regions include cobras (Naja spp.), carpet and saw-scaled vipers (Echis spp.), Russell's vipers (D. russelii), large African vipers (Bitis spp.), lancehead pit vipers (Bothrops spp.), and tropical rattlesnakes (C. durissus).

The incidence of morbidity—defined as permanent functional loss in a bitten extremity—is difficult to estimate but is substantial. Morbidity may be due to muscle, nerve, or vascular injury or to scar contracture. In the United States, such loss tends to be more common and severe after rattlesnake bites than after bites by copperheads (Agkistrodon contortrix) or water moccasins (A. piscivorus).

Eye Anatomy

2008-09-09T10:09:00.009+08:00

A Brief Anatomy of the Eye
Gray's Anatomy 39th

The eyeball, the peripheral organ of vision, is situated in a skeletal cavity, the orbit, the walls of which help to protect it from injury. The orbit also has a more fundamental role in the visual process itself, in providing a rigid support and direction to the eye and in forming the sites of attachment for its external muscles. This setting permits the accurate positioning of the visual axis under neuromuscular control, and determines the spatial relationship between the two eyes - essential for binocular vision and conjugate eye movements.

The eyeball is embedded in orbital fat, separated from it by a thin fascial sheath. It is composed of the segments of two spheres of different radii. The anterior segment, part of the smaller sphere, is transparent and forms c.7% of the surface of the whole globe. It is more prominent than the posterior segment, which is part of a larger sphere and opaque, and forms the remainder of the globe. The anterior segment is bounded by the cornea and the lens, and is incompletely subdivided into anterior and posterior chambers by the iris. These chambers are continuous through the pupil. The anterior chamber is slightly overlapped by the sclera peripherally. The angle between the iris and cornea therefore forms an annulus of greater diameter than the limbus, the junction between the sclera and cornea. The difference between these two varies from 1 to 2 mm, the angle being deeper above and below than at the sides of the eyeball. The posterior chamber lies between the posterior surface of the iris and the anterior aspect of the lens and its supporting ligament, the zonule, and is triangular in section. The apex of the triangle is the point where the iris touches the lens, and the base, or zonular region, extends among the collagenous bundles of the zonule, sometimes even into a retrozonular space between the zonule and the vitreous humour in the posterior segment of the eyeball. The posterior segment consists of the parts of the eye posterior to the zonule and lens.

The anterior pole is the centre of the anterior (corneal) curvature, and the posterior pole is the centre of its posterior (scleral) curvature; a line joining these two points forms the optic axis. (By the same convention, the eye has an equator, equidistant between the poles: any circumferential line joining the poles is a meridian.) The optic axes of the two eyes, in their primary position, are parallel and do not correspond with the orbital axes, which diverge anterolaterally at a marked angle to each other . The optic nerves follow the orbital axes and are therefore not parallel; each enters its eye c.3 mm medial (nasal) to the posterior pole. The ocular vertical diameter (23.5 mm) is rather less than the transverse and anteroposterior diameters (24 mm); the anteroposterior diameter at birth is c.17.5 mm and at puberty 20-21 mm; it may vary considerably in myopia (c.29 mm) and in hypermetropia (c.20 mm). In females all diameters are on average slightly less than in the male.

Figure 1 The organization of the eye, viewed from above. In this illustration the left eye and part of the lower eyelid are depicted in horizontal section and also cut away to show internal structure.

OCULAR FIBROUS TISSUE

The eye has three layers enclosing its contents. From the outer surface these are a fibrous layer, which consists of the sclera behind and the cornea in front; a vascular, pigmented layer which consists of (from behind forwards) the choroid, ciliary body and iris, collectively termed the uveal tract; and a neural layer, known as the retina.

The fibrous layer of the eyeball (Fig. 1) has an opaque posterior sclera and a transparent anterior cornea. Together these form the protective enclosing capsule of the eye, a semi-elastic structure which when made turgid by intraocular pressure, determines with great precision the optical geometry of the visual apparatus. The sclera also provides attachments for the extraocular muscles which rotate the eye, its smooth external surface rotating easily on the adjacent tissues of the orbit. The cornea admits light, refracts it towards a retinal focus, and plays an important role in the image-processing mechanism

OCULAR VASCULAR TUNIC

The vascular tunic, or uveal tract (Fig. 2), consists of the choroid, ciliary body and iris (Fig. 3), which collectively form a continuous structure. The choroid covers the internal scleral surface, and extends forwards to the ora serrata. The ciliary body continues forward from the choroid to the circumference of the iris, which is a circular diaphragm behind the cornea and in front of the lens. It presents an almost central aperture, the pupil

Figure 2 The vascular arrangements of the uveal tract. The long posterior ciliary arteries, one of which is visible (A), branch at the ora serrata (b) and feed the capillaries of the anterior part of the choroid. Short posterior ciliary arteries (C) divide rapidly to form the posterior part of the choriocapillaris. Anterior ciliary arteries (D) send recurrent branches to the choriocapillaris (e) and anterior rami to the major arterial circle (f). Branches from the circle extend into the iris (g) and to the limbus. Branches of the short posterior ciliary arteries (C) form an anastomotic circle (h) (of Zinn) round the optic disc, and twigs (i) from this join an arterial network on the optic nerve. The vorticose veins (J) are formed by the junctions (k) of suprachoroidal tributaries (l). Smaller tributaries are also shown (m, n). The veins draining the scleral venous sinus (o) join anterior ciliary veins and vorticose tributaries. (By permission from Hogan MJ, Alvarado JA, Weddell JE 1971 Histology of the Human Eye. Philadelphia: WB Saunders.)

Figure 3. Composite view of the surfaces and internal strata of the iris. In a clockwise direction from above, the pupillary (A) and ciliary (B) zones are shown in successive segments. The first (brown iris) shows the anterior border layer and the openings of crypts (c). In the second segment (blue iris), the layer is much less prominent and the trabeculae of the stroma are more visible. The third segment shows the iridial vessels, including the major arterial circle (e) and the incomplete minor arterial circle (f). The fourth segment shows the muscle stratum, including the sphincter (g) and dilator (h) of the pupil. The everted 'pupillary ruff' of the epithelium on the posterior aspect of the iris (d) appears in all segments. The final segment, folded over for pictorial purposes, depicts this aspect of the iris, showing radial folds (i and j) and the adjoining ciliary processes (k). (By permission from Hogan MJ, Alvarado JA, Weddell JE 1971 Histology of the Human Eye. Philadelphia: WB Saunders.)

RETINA

The retina is the sensory neural layer of the eyeball. It is a most complex structure and should be considered as a special area of the brain, from which it is derived by outgrowth from the diencephalon . It is dedicated to the detection and early analysis of visual information and is an integrated part of the much larger apparatus of visual analysis present in the thalamus, cortex and other areas of the central nervous system.

Layers of Retina

The retina is organized into layers or zones where distinctive components of its cells are clustered together or in register to form continuous strata. These layers extend uninterrupted throughout the photoreceptive retina except at the exit point of the optic nerve fibres at the optic disc, although certain layers are much reduced at the foveola where the photoreceptive elements predominate. The names given to the different layers reflect in part the components present within them, and also their position in the thickness of the retina. Conventionally, those structures furthest from the vitreous (i.e. towards the choroid) are designated as outer or external, and those towards the vitreous are inner or internal.

Customarily, ten retinal layers are distinguished (Fig. 4), beginning at the choroidal edge and passing towards the vitreous. These are: retinal pigment epithelium; layer of rods and cones (outer segments and inner segments); external limiting membrane; outer nuclear layer; outer plexiform layer (OPL); inner nuclear layer (INL); inner plexiform layer (IPL); ganglion cell layer; nerve fibre layer; internal limiting membrane. Some of these are subdivisible into substrata, and an innermost plexiform layer between layers 8 and 9 has also been demonstrated.

The composition of the different retinal layers is as follows:

Layer 1: Pigment epithelium

This is a simple low cuboidal epithelium which forms the back of the retina, and, therefore forms the boundary with the choroid, from which it is separated by a thick composite basal lamina.

Layer 2: Rod and cone cell processes

This contains the photoreceptive outer segments and the outer part of the inner segments of rod and cone cells.

Layer 3: External limiting membrane

This layer appears as a distinct line by light microscopy. It consists of a zone of intercellular junctions of the zonula adherens type (p. 7) between the processes of radial glial cells and photoreceptor processes.

Layer 4: Outer nuclear layer

This consists of several tiers of rod and cone cell bodies and their nuclei, the cone nuclei lying outermost. Mingled with these are the outer and inner fibres from the same cell bodies, directed outward to the bases of inner segments, and inwards towards the outer plexiform layer.

Layer 5: Outer plexiform layer

This is a region of complex synaptic arrangements between the processes of the cells whose cell bodies lie in the adjacent layers. The outer plexiform layer contains the synaptic processes of rod and cone cells, bipolar cells, horizontal cells, and some interplexiform cells (which in this account are grouped with the amacrines).

Layer 6: Inner nuclear layer

This is composed of three nuclear strata. Horizontal cell nuclei form the outermost zone, then in sequence inwards, the nuclei and cell bodies of bipolar cells, radial glial cells, and the outer set of amacrine cells, including the interplexiform cells whose dendrites cross this layer.

Layer 7: Inner plexiform layer

This is divisible into three layers depending on the types of contact occurring. The outer or 'OFF' layer contains synapses between 'OFF' bipolar cells, ganglion cells and some amacrines; a middle or 'ON' layer contains synapses between the axons of 'ON' bipolars and the dendrites of ganglion cells and displaced amacrines; and an inner 'rod' layer contains synapses between rod bipolars and displaced amacrines. (Refer to Wässle & Boycott 1991 for an explanation of the 'OFF' and 'ON' cell designations.)

Layer 8: Ganglion cell layer
This layer contains the nuclei of the displaced amacrine cells. Its inner regions consist of the cell bodies, nuclei and initial segments of retinal ganglion cells of various classes.

Layer 9: Nerve fibre layer

This contains the unmyelinated axons of retinal ganglion cells. It forms a zone of variable thickness over the inner retinal surface, and is the only component of the retina at the point where the fibres pass into the nerve at the optic disc. The inner aspect of this layer contains the nuclei and processes of astrocytes which, together with radial glial cells, ensheath the nerve fibres. Between the nerve fibre layer and the ganglion cells there is another narrow innermost plexiform layer where neuronal processes make synaptic contact with the axon hillocks and initial segments of ganglion cells.

Layer 10: Internal limiting membrane

This is a glial boundary between the retina and the vitreous body. It is formed by the end feet of radial glial cells and astrocytes, and is separated from the vitreous body by a basal lamina.

Figure 4 The layered arrangement of neuronal cell bodies in the retina and the interconnections of their processes in the intervening plexiform layers. Also shown are the two principal types of neuroglial cell in the retina; microglia are also present but not shown.

Optic disc

The optic disc is the region where retinal tissues meet the neural and glial elements of the optic nerve and the connective tissues of the sclera and meninges. It is the exit point for the optic nerve fibres, and a point of entry and exit for the retinal circulation. It is the only site where anastomoses occur with other arteries (the posterior ciliary arteries). It is visible, by ophthalmoscopy, and is a region of much clinical importance, since it is here that the central vessels can be inspected directly: the only vessels so accessible in the whole body. Oedema of the disc (papilloedema) may be the first sign of raised intracranial pressure, which is transmitted into the subarachnoid space around the optic nerve and compresses the central retinal vein where it crosses the space.

The optic disc is superomedial to the posterior pole of the eye, and so lies away from the visual axis. It is round or oval, usually c.1.6 mm in transverse diameter and 1.8 mm in vertical diameter, and its appearance is very variable (for details see Jonas et al 1988). In light-skinned subjects, the general retinal hue is a bright terracotta-red, with which the pale pink of the disc contrasts sharply; its central part is usually even paler and may be light grey. These differences are due in part to the degree of vascularization of the two regions, which is much less at the optic disc, and also to the total absence of choroidal or retinal pigment cells, since the retina is represented in the disc by little more than the internal limiting membrane. In subjects with strongly melanized skins, both retina and disc are darker . The optic disc does not project at all in many eyes, and rarely does it project sufficiently to justify the term papilla. It is usually a little elevated on its lateral side, where the papillomacular nerve fibres turn into the optic nerve. There is usually a slight depression where the retinal vessels traverse its centre.

RETINAL VASCULAR SUPPLY

The central retinal artery enters the optic nerve as a branch of the ophthalmic artery, c.1.2 cm behind the eyeball. It travels in the optic nerve to its head, where its fascicles traverse the lamina cribrosa. At this level, which is usually not visible to ophthalmoscopy, the central artery divides into two equal branches, superior and inferior. After a few millimetres, these divide into superior and inferior nasal, and superior and inferior temporal, branches. Each of these four supplies its own 'quadrant' of the retina, although each territory is much more than a quadrant, since the branches ramify as far as the ora serrata. Corresponding retinal veins unite to form the central retinal vein. However, the courses of the venous and arterial vessels do not correspond exactly, and arteries often cross veins, usually lying superficial to them. In severe hypertension the arteries may press on the veins and cause visible dilations distal to these crossings. Arterial pulsation is not visible by routine ophthalmoscopy without higher magnification.

The branching of the artery is usually dichotomous, and equal rami diverge at angles of 45-60°. Smaller branches may leave singly and at right angles. Arteries and veins ramify in the nerve fibre layer, near the internal limiting membrane, which accounts for their clarity when seen through an ophthalmoscope . Arterioles pass deeper into the retina and may penetrate to the internal nuclear lamina, from which venules return to larger superficial veins. The question of whether or not the dense capillary bed is diffusely organized or layered is unsettled. Some lamination has been identified, most noticeably at the interface between the inner nuclear and outer plexiform layers. The structure of the blood vessels resembles that of vessels elsewhere, except that the internal elastic lamina is absent from the arteries, and muscle cells may appear in their adventitia. Capillaries have a non-fenestrated endothelium.

OCULAR REFRACTIVE MEDIA

The components of the eye that transmit and refract light are the cornea, the aqueous humour, the lens and the vitreous body. Of these, only the refracting power of the lens can be varied.

Aqueous humour

To satisfy the requirements of vision the eye has its own circulatory system. Aqueous humour is secreted into the posterior chamber by the non-pigmented epithelium of the ciliary processes. It passes into the anterior chamber through the pupil and drains to the scleral venous sinus at the iridocorneal angle through the spaces of the trabecular tissue. It is responsible for maintaining the metabolism of the avascular transparent media, vitreous, lens and cornea, and it also maintains and regulates the relatively high intraocular pressure (c.17 mmHg), and hence the constancy of the ocular dimensions of the eyeball, via the balance between production and drainage. Depth of the anterior chamber may be assessed using slit-lamp biomicroscopy, and the filtration angle may be viewed directly by gonioscopy. Any interference with its drainage into the sinus increases intraocular pressure leading to the condition of glaucoma.

Lens

The lens is a transparent, encapsulated, biconvex body, which lies between the iris and the vitreous body. Posteriorly, the lens contacts the hyaloid fossa (p. 719) of the vitreous body. Anteriorly, it forms a ring of contact with the free border of the iris, but further away from the axis of the lens the gap between the two increases to form the posterior chamber of the eye (p. 708). The lens is encircled by the ciliary processes, and is attached to them by the zonular fibres which issue mainly from the pars plana of the ciliary body. Collectively, the fibres form the zonule which holds the lens in place and transmits the forces which stretch the lens (except in visual accommodation).

The lens has a characteristic shape. Its anterior convexity is less steep, and has a greater radius of curvature, than the posterior, which has a more parabolic shape. The central points of these surfaces are the anterior and posterior poles; a line connecting these is the axis of the lens. The marginal circumference of the lens is its equator. In fetuses the lens is nearly spherical, has a slight reddish tinge, and is soft, such that it breaks up on application of the slightest pressure. A hyaloid artery from the central retinal artery traverses the vitreous body to the posterior pole of the lens, whence its branches spread as a plexus. This covers the posterior surface and is continuous round the capsular circumference with the vessels of the pupillary membrane and iris.

In infants and adults the lens is avascular, colourless and transparent, but still quite soft in texture. In old age, the anterior surface becomes a little more curved, which pushes the iris forward slightly. It becomes less clear, with an amber tinge, and its nucleus is denser. In cataract, the lens gradually becomes opaque, causing blindness.

The dimensions of the lens are optically and clinically important, but they change with age as a consequence of continuous growth. Its equatorial diameter at birth is 6.5 mm, increasing rapidly at first, then more slowly to 9.0 mm at 15 years of age, and even more gradually to reach 9.5 mm in the ninth decade. Its axial dimension increases from 3.5-4.0 mm at birth to 4.75-5.0 mm at age 95. The radii of curvature reduce throughout life; the anterior surface shows the greater change as the lens thickens (Brown 1974). Average adult radii of the anterior and posterior surfaces are 10 mm and 6 mm respectively; the reduction during accommodation occurs mainly at the anterior surface.

Vitreous body

The vitreous body fills the vitreous chamber, and occupies about four-fifths of the eyeball. It is hollowed in front as a deep concavity, the hyaloid fossa, which is adapted to the lens. It is colourless, consisting of c.99% water, but not entirely structureless. At its perimeter it has a gel-like consistency (100-300μm thick) and is firmly attached to the surrounding structures of the eye; nearer the centre it has a more liquid zone in the form of long glycosaminoglycan chains, fills the whole vitreous. In addition, the peripheral gel or cortex contains a random loose network of type II collagen fibrils which are occasionally grouped into fibres. The cortex also contains scattered cells, the hyalocytes, which possess the characteristics of mononuclear phagocytes. They are responsible for the production of . Whilst they are normally in a resting state, they have the capacity to be actively phagocytic in inflammatory conditions. Hyalocytes are not present in the cortex bordering the lens. The liquid vitreous is absent at birth, appears first at 4 or 5 years, and increases to occupy half the vitreous space by the seventh decade. The cortex is most dense at the pars plana of the ciliary body adjacent to the ora serrata, where attachment is strongest, and this is often referred to as the base of the vitreous. Here the vitreous is thickened into a mass of radial (zonular) fibres which form the suspensory ligament of the lens

A narrow hyaloid canal runs from the optic nerve head to the central posterior surface of the lens. In the fetus this contains the hyaloid artery which normally disappears about 6 weeks before birth. It persists as a very delicate fibrous structure and is of no functional importance.

Retinal Detachment

2008-09-07T23:05:00.003+08:00

Retinal Detachment and Related Retinal Degenerations
Vaughan & Asbury's General Ophthalmology 17th Edition

Retinal detachment is the separation of the sensory retina, ie, the photoreceptors and inner tissue layers, from the underlying retinal pigment epithelium. There are three main types: rhegmatogenous, traction, and serous or hemorrhagic detachment.

Rhegmatogenous Retinal Detachment

The most common type of retinal detachment, rhegmatogenous retinal detachment is characterized by a full-thickness break (a "rhegma") in the sensory retina, variable degrees of vitreous traction, and passage of liquefied vitreous through the break into the subretinal space. A spontaneous rhegmatogenous retinal detachment is usually preceded or accompanied by a posterior vitreous detachment and is associated with myopia, aphakia, lattice degeneration, and ocular trauma. Binocular indirect ophthalmoscopy with scleral depression reveals elevation of the translucent detached sensory retina with one or more full-thickness sensory retinal breaks, such as a horseshoe tear, round atrophic hole, or anterior circumferential tear (retinal dialysis). The location of retinal breaks varies according to type; horseshoe tears are most common in the superotemporal quadrant, atrophic holes in the temporal quadrants, and retinal dialysis in the inferotemporal quadrant. When multiple retinal breaks are present, the defects are usually within 90 degrees of one another.

Figure 1. Retinal Detachment

Treatment

The principal aims of detachment surgery are to find and treat all the retinal breaks, cryotherapy or laser being applied to create an adhesion between the pigment epithelium and the sensory retina, thus preventing any further influx of fluid into the subretinal space, to drain subretinal fluid, internally or externally, and relieve vitreo-retinal traction. Various surgical techniques are employed.

In pneumatic retinopexy air or expandable gas is injected into the vitreous to maintain the retina in position, while the chorioretinal adhesion induced by laser or cryotherapy achieves permanent closure of the retinal break. It has a lower success rate than other methods and is used only when there is a small accessible single retinal break, minimal subretinal fluid, and no vitreo-retinal traction.

Scleral buckling maintains the retina in position, while the chorioretinal adhesion forms, by indenting the sclera with a sutured explant in the region of the retinal break. This also relieves vitreo-retinal traction and displaces subretinal fluid away from the retinal break. The success rate is 92–94% in suitably selected cases. Complications include change in refractive error, diplopia due to fibrosis or involvement of extraocular muscles in the explant, extrusion of the explant, and possibly increased risk of proliferative vitreoretinopathy.

Pars plana vitrectomy allows relief of vitreo-retinal traction, internal drainage of subretinal fluid, if necessary by injection of perfluorocarbons or heavy liquids, and injection of air or expandable gas to maintain the retina in position, or injection of oil if longer-term tamponade or the retina is required. It is used if there are superior, posterior, or multiple retinal breaks, when visualization of the retina is inhibited, such as by vitreous hemorrhage, and if there is significant proliferative vitreoretinopathy. Vitrectomy induces cataract formation and may be contraindicated in phakic eyes. Postoperative posturing may be required.

The visual results of surgery for rhegmatogenous retinal detachment primarily depend on the preoperative status of the macula. If the macula has been detached, recovery of central vision is usually incomplete. Thus, surgery should be performed urgently if the macula is still attached. Once the macula is detached, delay in surgery for up to 1 week does not adversely influence visual outcome.

Traction Retinal Detachment

Traction retinal detachment is most commonly due to proliferative diabetic retinopathy. It can also be associated with proliferative vitreoretinopathy, retinopathy of prematurity, or ocular trauma. In comparison to rhegmatogenous retinal detachment, traction retinal detachment has a more concave surface and is likely to be more localized, usually not extending to the ora serrata. The tractional forces actively pull the sensory retina away from the underlying pigment epithelium toward the vitreous base. Traction is due to formation of vitreal, epiretinal, or subretinal membranes consisting of fibroblasts and glial and retinal pigment epithelial cells. Initially the detachment may be localized along the vascular arcades, but progression may spread to involve the midperipheral retina and the macula. Focal traction from cellular membranes can produce a retinal tear and lead to combined traction-rhegmatogenous retinal detachment.

Proliferative vitreoretinopathy is a complication of rhegmatogenous retinal detachment and is the most common cause of failure of surgical repair in these eyes.

Figure 2. Retinal Detachment

Treatment

Pars plana vitrectomy allows removal of the tractional elements followed by removal of the fibrotic membranes. Retinotomy and/or injection of perfluorocarbons or heavy liquids may be required to flatten the retina. Gas tamponade, silicone oil, or scleral buckling may be used.

Serous & Hemorrhagic Retinal Detachment

Serous and hemorrhagic retinal detachment occurs in the absence of either retinal break or vitreoretinal traction. They form as a result of accumulation of fluid beneath the sensory retina and are caused primarily by diseases of the retinal pigment epithelium and choroid. Degenerative, inflammatory, and infectious diseases, including the multiple causes of subretinal neovascularization, may be associated with serous retinal detachment and are described in an earlier section of this textbook. This type of detachment may also be associated with systemic vascular and inflammatory disease, or intraocular tumors.

Lattice Degeneration

Lattice degeneration is the most common vitreoretinal degeneration. The estimated incidence in the general population is 6–10%, of which up to 50% have bilateral disease. It is more commonly found in myopic eyes with some familial tendency. It produces localized round, oval, or linear areas of retinal thinning, with pigmentation, branching white lines, and whitish-yellow flecks, and firm vitreoretinal adhesions at its margins. Lattice degeneration results in retinal detachment in only a small percentage of affected eyes, but 20–30% of eyes with retinal detachment have lattice degeneration. Strong family history of retinal detachment, retinal detachment in the fellow eye, high myopia, and aphakia require the patient to be informed of the risks of retinal detachment and the relevant symptoms but rarely warrant prophylactic treatment with cryosurgery or laser photocoagulation.

Peripheral Chorioretinal Atrophy

Peripheral chorioretinal atrophy (paving stone degeneration) is a common benign chorioretinal degeneration found in nearly one-third of adult eyes. It is thought to be due to choroidal vascular insufficiency and is associated with peripheral vascular disease. The lesions appear as isolated or grouped, small, discrete, yellow-white areas with prominent underlying choroidal vessels and pigmented borders.

Retinoschisis

Degenerative retinoschisis is a common acquired peripheral retinal disorder that is believed to develop from coalescence of preexisting peripheral cystoid degeneration. The cystic elevation is most commonly found in the inferotemporal quadrant, followed by the superotemporal quadrant. It develops into one of two forms, typical or reticular, although clinically the two are difficult to differentiate.

Typical degenerative retinoschisis forms a round or ovoid area of retinal splitting in the outer plexiform layer. Posterior extension and hole formation in the outer layer is uncommon and therefore poses low risk of progression to retinal detachment.

Reticular degenerative retinoschisis is characterized by round or oval areas of retinal splitting in the nerve fiber layer forming a bullous elevation of an extremely thin inner layer. Retinal holes occur in 23%, and posterior extension or progression to rhegmatogenous retinal detachment may occur and requires treatment.

Natural History

Degenerative retinoschisis is present in about 4% of the population and is bilateral in approximately 30% of affected individuals. Spontaneous regression occurs in up to 9% of cases. Progression to retinal detachment occurs in up to 2%, with increased risk for those with a family history of retinal detachment. Whether cataract extraction increases the risk of retinal detachment is uncertain. Retinal detachment occurs in one of two ways. A hole in the outer but not the inner retinal layer allows the cystic fluid through the defect. This type is usually not or is only slowly progressive, and therefore a demarcation line forms. It rarely requires treatment. In the second type, holes form in both the inner and the outer layers. This causes collapse of the schisis and full retinal detachment forms. Progression is quick, and treatment is required by pneumatic retinopexy, scleral buckle, or vitrectomy, depending on the size and position of the retinal holes and whether there is any proliferative vitreoretinopathy.

Differentiation from Retinal Detachment

Retinoschisis causes an absolute scotoma in the visual field, whereas retinal detachment causes a relative scotoma. The cystic elevation of retinoschisis is usually smooth with no associated vitreous pigment cells. The surface of retinal detachment is usually corrugated with pigment cells in the vitreous ("tobacco dust"). Longstanding retinal detachment produces atrophy of the underlying retinal pigment epithelium, resulting in a pigmented demarcation line. As the retinal pigment epithelium is healthy in retinoschisis, there is no demarcation line. If argon laser photocoagulation to the outer retinal layer, aimed through an inner layer break, creates an equal gray response as in an adjacent area of normal retina, this is thought to be diagnostic of retinoschisis.

Pediatric AIDS

2008-09-05T16:28:00.009+08:00

Acquired Immunodeficiency Syndrome
(Human Immunodeficiency Virus)
Ram, Yogev Ellen, Gould Chadwick - Nelson Pediatric 18th Ed. 2007

Advances in research and major improvements in the treatment and management of HIV infection have brought about a substantial decrease in the incidence of new HIV infections and AIDS in children born in the United States and Western Europe. Most HIV-infected children are born in developing countries. It is estimated that in 2004, 640,000 children <15>

ETIOLOGY.

HIV-1 and HIV-2 are members of the Retroviridae family and belong to the Lentivirus genus, which includes cytopathic viruses causing diverse diseases in several animal species. The HIV-1 genome contains 2 copies of single-stranded RNA that is 9.2 kb in size. At both ends of the genome there are identical regions, called long terminal repeats, which contain the regulation and expression genes of HIV. The remainder of the genome includes 3 major sections: the GAG region, which encodes the viral core proteins (p24, p17, p9, p6, which are derived from the precursor p55); the POL region, which encodes the viral enzymes (i.e., reverse transcriptase [p51], protease [pl0], and integrase [p32]); and the ENV region, which encodes the viral envelope proteins (gp120 and gp41, which are derived from the precursor gp160). Other regulatory proteins, such as tat (pl4), rev (p19), nef (p27), vpr (pl5), and vif (p23), are involved in transactivation, viral messenger RNA expression, viral replication, induction of cell cycle arrest, promotion of nuclear import of viral reverse transcription complexes, downregulation of cell surface receptors CD4 and class I major histocompatibility complex, proviral DNA synthesis, and virus release ( Fig. 1 ).

Figure 1 The human immunodeficiency virus and associated proteins and their functions

The major external viral protein of HIV-1 is a heavily glycosylated gp120 protein that is associated with the transmembrane glycoprotein gp41; gp41 is very immunogenic and is used to detect HIV-1 antibodies in diagnostic assays; gp120 is a complex molecule that includes the highly variable V3 loop. This region is immunodominant for neutralizing antibodies. The heterogeneity of gp120 presents major obstacles in establishing an effective HIV vaccine. The gp120 glycoprotein also carries the binding site for the CD4 molecule, the most common host cell surface receptor of T lymphocytes. This tropism for CD4+ T cells is beneficial to the virus because it reduces the effectiveness of the host immune system. Other CD4-bearing cells include macrophages and microglial cells. Several chemokines serve as co-receptors for the envelope glycoproteins, permitting membrane fusion and entry into the cell. Most HIV strains have a specific tropism for 1 of the chemokines, including the fusion-inducing molecule CXCR-4, which has been shown to act as a co-receptor for HIV attachment to lymphocytes, and CCR-5, a β chemokine receptor that facilitates HIV entry into macrophages. Several other chemokine receptors (CCR-3) have also been shown in vitro to serve as virus co-receptors.

Other mechanisms of attachment of HIV to cells use non-neutralizing antiviral antibodies and complement receptors. The Fab portion of these antibodies attaches to the virus surface, and the Fc portion binds to cells that express Fc receptors (macrophages, fibroblasts), thus facilitating virus transfer into the cell. Other cell surface receptors, such as mannose-binding protein on macrophages and DC-specific C-type lectin (DC-SIGN) on dendritic cells, also bind to the HIV-1 envelope glycoprotein and increase the efficiency of viral infectivity. Following viral attachment, gp120 and the CD4 molecule undergo conformational changes, and gp41 interacts with the fusion receptor on the cell surface. Viral fusion with the cell membrane allows entry of viral RNA into the cell cytoplasm. This process involves accessory viral proteins (nef, vif) and binding of cyclophilin A (a host cellular protein) to p24. Viral DNA copies are then transcribed from the virion RNA through viral reverse transcriptase enzyme activity, and duplication of the DNA copies produces double-stranded circular DNA. The HIV-1 reverse transcriptase is error prone and lacks error-correcting mechanisms. Thus, many mutations arise, creating wide genetic variation in HIV-1 isolates even within an individual patient. The circular DNA is transported into the cell nucleus, where it is integrated into chromosomal DNA and referred to as the provirus. The provirus has the advantage of latency as it can remain dormant for extended periods. Integration usually occurs near active genes, which allow a high level of viral production in response to various external factors such as an increase in inflammatory cytokines (by infection with other pathogens) and cellular activation. Depending on the relative expression of the viral regulatory genes (tat, rev, nef), the proviral DNA may encode production of the viral RNA genome, which in turn leads to production of viral proteins necessary for viral assembly.

HIV-1 transcription is followed by translation. A capsid polyprotein is cleaved to produce, among others, the virus-specific protease (p10). This enzyme is critical for HIV-1 assembly. Several HIV-1 antiprotease drugs have been developed, targeting the increased sensitivity of the viral protease, which differs from the cellular proteases. The RNA genome is then incorporated into the newly formed viral capsid that requires zinc finger domains (p7) and the matrix protein (p17). As new virus is formed, it buds through specialized membrane areas, known as lipid rafts, and is released.

The diversity of HIV (groups M [main], O [outlier], N [non-M, non-O]) probably occurred from multiple zoonotic infections from primates in different geographic regions. Group M diversified to several subtypes (or clades A to H). In each region of the world, certain clades predominate. For example, clade B is found in the United States and South America, clade E in Thailand, and clade C in South Africa. Clades are mixed in some patients due to HIV recombination, and some crossing between groups (i.e., M and O) has been reported.

HIV-2 is known to cause infection in several monkey species. It is a rare cause of infection in children. It is most prevalent in Western Africa, but recently cases from Europe and Southern Asia have been reported. The diagnosis of HIV-2 infection is more difficult because the standard confirmatory assays (immunoblot) are HIV-1 specific and may give indeterminate results with HIV-2 infection. If HIV-2 infection is suspected, a specific immunoblot test that detects antibody to HIV-2 peptides should be used. In addition, the recently approved rapid tests should not be used in patients suspected to be HIV-2 infected because they test only for HIV-1. Third generation standard enzyme-linked immunosorbent assays (ELISA) should be used because they capture both HIV-1 and HIV-2.

EPIDEMIOLOGY.

The World Health Organization (WHO) estimated that >39 million persons worldwide were living with HIV infection at the end of 2004, including 2.2 million children <15>500,000 and 9% in metropolitan areas with populations of 50,000–500,000.

Although adolescents (13–24 yr of age) with AIDS represent a minority of U.S. cases (approximately 5%), they constitute 1 of the fastest growing groups of newly infected persons in the country. Considering the long latency period between the time of infection and the development of clinical symptoms, reliance on AIDS case definition surveillance data severely under-represents the impact of the disease in adolescents. Based on a median incubation period of 8–12 yr, it has been estimated that 15–20% of all AIDS cases were acquired between 13 and 19 yr of age. Risk factors for HIV infection vary by gender in adolescents. The majority of teenaged males with AIDS who acquired HIV through sexual contact had male-to-male transmission. In contrast, more than half of adolescent females with AIDS were infected through heterosexual contact and ⅙ through IDU, compared with 8% and 6%, respectively, in teenaged males.

As in the pediatric population, adolescent racial and ethnic minority populations are over-represented, especially among females. In addition, a greater proportion of female adolescents have AIDS (male : female ratio 1.2 : 1) than do female adults >25 yr of age (male : female ratio 4.5 : 1).

Transmission.

Transmission of HIV-1 occurs via sexual contact, parenteral exposure to blood, or vertical transmission from mother to child. The primary route of infection in the pediatric population is vertical transmission, accounting for almost all new cases. Rates of transmission of HIV from mother to child have varied in different parts of the United States and among countries. The United States and Europe have documented transmission rates in untreated women between 12–30%. Transmission rates in Africa and Haiti are higher (25–52%). Perinatal treatment of HIV-infected mothers with anti-retroviral drugs has dramatically decreased these rates to <2%>4 hr duration of ruptured membranes and birthweight <2,500>50,000 copies/mL), some transmitting mothers in each group were asymptomatic or had a low, but detectable, viral load. Thus, in the USA it is recommended to consider cesarean section if the viral load is >1,000 copies/mL.

Transfusions of infected blood or blood products have accounted for 3–6% of all pediatric AIDS cases. The period of highest risk was between 1978 and 1985, before the availability of HIV antibody-screened blood products. Whereas the prevalence of HIV infection in individuals with hemophilia treated before 1985 was as high as 70%, heat treatment of factor VIII concentrate and HIV antibody screening of donors has virtually eliminated HIV transmission in this population. Blood donor screening has dramatically reduced, but not eliminated, the risk for transfusion-associated HIV infection. The rate of HIV transmission through antibody-screened blood in the USA is estimated to be approximately 1/60,000 transfused units. In many developing countries, screening of blood donors is not uniform, and the risk for transmitting HIV infection via transfusion is substantial.

Although HIV can be isolated rarely from saliva, it is in very low titers

PATHOGENESIS.

When the mucosa serves as the portal of entry for the HIV, the 1st cells to be infected are the dendritic cells. These cells collect and process antigens introduced from the periphery and transports them to the lymphoid tissue. 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 virus selectively binds to cells expressing CD4 molecules on their surface, primarily helper T lymphocytes (CD4 cells) and cells of the monocyte-macrophage lineage. Other cells bearing CD4, such as microglia, astrocytes, oligodendroglia, and placental tissue containing villous Hofbauer cells, may also be infected by HIV. Additional factors (co-receptors) are necessary for HIV fusion and entry into cells. These factors include the chemokines CXCR4 (fusion) and CCR5. Other chemokines (CCR1, CCR3) may be necessary for the fusion of certain HIV strains. Individuals with homozygous CCR5 deletion mutation are highly protected from HIV infection. 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. HIV preferentially infects the very cells that respond to it (HIV-specific memory CD4 cells), which accounts for the progressive loss of these cells' response and the subsequent loss of control of HIV replication. When HIV replication reaches a threshold (usually within 3–6 wk from the time of infection), a burst of plasma viremia occurs. This intense viremia causes flulike symptoms (fever, rash, lymphadenopathy, arthralgia) in 50–70% of infected adults. With establishment of a cellular and humoral immune response within 2–4 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.

Early HIV-1 replication in children has no apparent clinical manifestations. Whether tested by virus isolation or by PCR for viral nucleic acid sequences, fewer than 50% of HIV-1-infected infants demonstrate evidence of the virus at birth. The virus load increases by 1–4 mo, and almost all HIV-infected infants have detectable HIV-1 in peripheral blood by 4 mo of age.

In adults, the long period of clinical latency (up to 8–12 yr) is not indicative of viral latency. In fact, there is a very high turnover of virus and CD4 lymphocytes (more than a billion cells per day), which gradually causes deterioration of the immune system, evidenced particularly by depletion of CD4 cells. Several mechanisms for the depletion of CD4 cells in adults and children have been suggested, including HIV-mediated single cell killing, formation of multinucleated giant cells of infected and uninfected CD4 cells (syncytia formation), virus-specific immune responses (natural killer cells, antibody-dependent cellular cytotoxicity), superantigen-mediated activation of T cells (rendering them more susceptible to infection with HIV), autoimmunity, and programmed cell death (apoptosis). The viral burden in the lymphoid organs is greater than that in the peripheral blood during the asymptomatic period. As HIV virions and their immune complexes migrate through the lymph nodes, they are trapped in the network of dendritic follicular cells. Because the ability of HIV to replicate in T cells depends on the state of activation of the cells, the immune activation that takes place within the microenvironment of the nodes in HIV disease serves to promote infection of new CD4 cells as well as subsequent viral replication within the cells. 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. CD8 T cells play an important role in containing the infection. These cells produce various ligands (MIP-1α, MIP-1β, RANTES), which suppress HIV replication by blocking the binding of the virus to the co-receptors (CCR5). HIV-specific cytotoxic T lymphocytes (CTLs) develop against both the structural (ENV, POL, GAG) and regulatory (tat) viral proteins. The CTLs appear at the end of the acute retroviral infection as the viral replication is controlled by killing HIV-infected cells before new viruses are produced and by secreting potent antiviral factors that compete with the virus for its receptors (CCR5). Neutralizing antibodies appear later during the infection and seem to help in the continued suppression of viral replication during clinical latency. There are at least 2 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 (controlled) replication. The other mechanism, the immune control, suggests that the development of an active immune response (whose magnitude is controlled by the amount of viral antigen) limits viral replication at a steady state. There is no general consensus about which of these 2 mechanisms is more important. The CD4 cell limitation mechanism accounts for the effect of anti-retroviral therapy, whereas the immune control mechanism emphasizes the importance of immune modulation treatment (cytokines, vaccines) to increase the efficiency of the immune response, which, in turn, slows disease progression.

A group of cytokines, such as tumor necrosis factor-α (TNF-α), TNF-β, interleukin 1 (IL-1), IL-2, IL-3, IL-6, IL-8, IL-12, IL-15, granulocyte-macrophage colony-stimulating factor, 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-γ (IFN-γ), IFN-β, and IL-13, exert a suppressive effect on HIV replication. Certain cytokines (IL-4, IL-10, IFN-γ, TGF-β) reduce or enhance viral replication depending on the infected cell type. 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 HIV isolated during the clinical latency period grows slowly in culture and produces low titers of reverse transcriptase. These isolates are called non-syncytium-inducing (NSI) viruses, which use CCR5 as their co-receptor. By the late stages of 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) 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.

Before HAART was available, 3 distinct patterns of disease were described in children. Approximately 15–25% of HIV-infected newborns in developed countries present with a rapid disease course, with onset of AIDS and symptoms during the 1st few months of life and, if untreated, a median survival time of 6–9 mo. In resource-poor countries, the majority of HIV-infected newborns will have this rapidly progressing disease. It has been suggested that if intrauterine infection coincides with the period of rapid expansion of CD4 cells in the fetus, it could effectively infect the majority of the body's immunocompetent cells. The normal migration of these cells to the marrow, spleen, and thymus would result in efficient systemic delivery of HIV, unchecked by the immature immune system of the fetus. Thus, infection would be established before the normal ontogenic development of the immune system, causing more severe impairment of immunity. Most children in this group have a positive HIV-1 culture and/or detectable virus in the plasma (median level 11,000 copies/mL) in the 1st 48 hr of life. This early evidence of viral presence suggests that the newborn was infected in utero. The viral load rapidly increases and peaks by 2–3 mo of age (median 750,000 copies/mL) and subsequently declines slowly. In contrast to the viral load in adults, the viral load in infants stays high for at least the 1st 2 yrs of life.

The majority of perinatally infected newborns (60–80%) in developed countries present with a 2nd pattern, that of a much slower progression of disease, with a median survival time of 6 yr. Many patients in this group have a negative viral culture or PCR in the 1st wk of life and are therefore considered to be infected intrapartum. In a typical patient, the viral load rapidly increases by 2–3 mo of age (median 100,000 copies/mL) and slowly declines over a period of 24 mo. The slow decline in viral load is in sharp contrast to the rapid decline after primary infection seen in adults. This observation can be explained only partially by the immaturity of the immune system in newborns and infants.

The 3rd pattern of disease (long-term survivors) occurs in a small percentage (<5%) style="font-weight: bold; color: rgb(204, 0, 0);">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. Whereas systemic and pulmonary findings are common in the USA and Europe, chronic diarrhea, wasting, and severe malnutrition predominate in Africa. 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.

The HIV classification system is used to categorize the stage of pediatric disease by using 2 parameters: clinical status and degree of immunologic impairment ( Table 1 ). Among the clinical categories, category A (mild symptoms) includes children with at least 2 mild symptoms such as lymphadenopathy, parotitis, hepatomegaly, splenomegaly, dermatitis, and recurrent or persistent sinusitis or otitis media ( Table 2 ). Category B (moderate symptoms) includes, for example, children with LIP, oropharyngeal thrush persisting for >2 mo, recurrent or chronic diarrhea, persistent fever for >1 mo, hepatitis, recurrent herpes simplex virus (HSV) stomatitis or HSV esophagitis or pneumonitis, disseminated varicella (i.e., with visceral involvement), cardiomegaly, or nephropathy (see Table 2 ). Category C (severe symptoms) includes, for example, children with 2 serious bacterial infections (sepsis, meningitis, pneumonia) in a 2 yr period, esophageal or lower respiratory tract candidiasis, cryptococcosis, cryptosporidiosis (>1 mo), encephalopathy, malignancies, disseminated mycobacterial infection, Pneumocystis pneumonia, cerebral toxoplasmosis (onset >1 mo of age), and severe weight loss.

The immune classification is based on the absolute CD4 lymphocyte count or the percentage of CD4 cells (see Table 1 ). Age adjustment of the absolute CD4 count is necessary because counts that are relatively high in normal infants decline steadily until 6 yr of age, when they reach adult norms. If there is a discrepancy between the CD4 count and percentage, the disease is classified into the more severe category.

TABLE 1 -- Pediatric HIV Classification for Children Younger Than 13 Years

	IMMUNOLOGIC CATEGORIES
	*AGE-SPECIFIC CD4+ T-LYMPHOCYTE COUNT PERCENTAGE OF TOTAL LYMPHOCYTES^[]**						CLINICAL CLASSIFICATIONS^[†]
	<12>		1–5 yr		6–12 yr
IMMUNOLOGIC DEFINITIONS	μ	%	μ	%	μ	%	N*	A*	*B^[‡]**	*C^[‡]**
1: No evidence of suppression	≥1500	≥25	≥1000	≥25	≥500	≥25	N1	A1	B1	C1
2: Evidence of moderate suppression	750–1499	15–24	500–999	15–24	200–499	15–24	N2	A2	B1	C2
3: Severe suppression	<750	<15	<500	<15	<200	<15	N3	A3	B3	C3

*N : No sign or symptom, A : Mild signs or symptoms, B : Moderate Signs or symptoms, C : Severe signs or symptoms

Modified from the Centers for Disease Control and Prevention: 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. Official authorized addenda: Human immunodeficiency virus infection codes and official guidelines for coding and reporting ICD-9-CM.MMWR Recomm Rep 1994;43(RR-12):1–19. Red Book: 2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2006, p 382.

^*	To convert values in ìL to Système International units (×109/L), multiply by 0.001.
^†	Children whose HIV infection status is not confirmed are classified by using this grid with a letter E (for perinatally exposed) placed before the appropriate classification code (eg, EN2).
^‡	Lymphoid interstitial pneumonitis in category B or any condition in category C is reportable to state and local health departments as acquired immunodeficiency syndrome (AIDS-defining conditions) (see Table 2 for further definition of clinical categories)

TABLE 2 -- Clinical Categories for Children Younger Than 13 Years of Age with HIV infection

		CATEGORY N: NOT SYMPTOMATIC
		Children who have no signs or symptoms considered to be the result of HIV infection or have only 1 of the conditions listed in category A.
		CATEGORY A: MILDLY SYMPTOMATIC
		Children with 2 or more of the conditions listed but none of the conditions listed in categories B and C.
	•	Lymphadenopathy (≥0.5 cm at more than 2 sites; bilateral at 1 site)
	•	Hepatomegaly
	•	Splenomegaly
	•	Dermatitis
	•	Parotitis
	•	Recurrent or persistent upper respiratory tract infection, sinusitis, or otitis media
		CATEGORY B: MODERATELY SYMPTOMATIC
		Children who have symptomatic conditions other than those listed for category A or C that are attributed to HIV infection.
	•	Anemia (hemoglobin <8>
	•	Bacterial meningitis, pneumonia, or sepsis (single episode)
	•	Candidiasis, oropharyngeal (thrush), persisting (>2 mo) in children older than 6 mo of age
	•	Cardiomyopathy
	•	Cytomegalovirus infection, with onset before 1 mo of age
	•	Diarrhea, recurrent or chronic
	•	Hepatitis
	•	Herpes simplex virus (HSV) stomatitis, recurrent (>2 episodes within 1 year)
	•	HSV bronchitis, pneumonitis, or esophagitis with onset before 1 mo of age
	•	Herpes zoster (shingles) involving at least 2 distinct episodes or more than 1 dermatome
	•	Leiomyosarcoma
	•	Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex
	•	Nephropathy
	•	Nocardiosis
	•	Persistent fever (lasting >1 mo)
	•	Toxoplasmosis, onset before 1 mo of age
	•	Varicella, disseminated (complicated chickenpox)
		CATEGORY C: SEVERELY SYMPTOMATIC
	•	Serious bacterial infections, multiple or recurrent (i.e. any combination of at least 2 culture-confirmed infections within a 2 yr period), of the following types: septicemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity (excluding otitis media, superficial skin or mucosal abscesses, and indwelling catheter-related infections)
	•	Candidiasis, esophageal or pulmonary (bronchi, trachea, lungs)
	•	Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or hilar lymph nodes)
	•	Cryptococcosis, extrapulmonary
	•	Cryptosporidiosis or isosporiasis with diarrhea persisting >1 mo
	•	Cytomegalovirus disease with onset of symptoms after 1 mo of age (at a site other than liver, spleen, or lymph nodes)
	•	Encephalopathy (at least 1 of the following progressive findings present for at least 2 mo in the absence of a concurrent illness other than HIV infection that could explain the .ndings): (1) failure to attain or loss of developmental milestones or loss of intellectual ability, veri.ed by standard developmental scale or neuropsychologic tests; (2) impaired brain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophy demonstrated by CT or MRI (serial imaging required for children younger than 2 yr of age); or (3) acquired symmetric motor deficit manifested by 2 or more of the following: paresis, pathologic reflexes, ataxia, or gait disturbance
	•	HSV infection causing a mucocutaneous ulcer that persists for greater than 1 mo or bronchitis, pneumonitis or esophagitis for any duration affecting a child older than 1 mo of age
	•	Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes)
	•	Kaposi sarcoma
	•	Lymphoma, primary, in brain
	•	Lymphoma, small, noncleaved cell (Burkitt), or immunoblastic; or large-cell lymphoma of B-lymphocyte or unknown immunologic phenotype
	•	Mycobacterium tuberculosis infection, disseminated or extrapulmonary
	•	Mycobacterium, other species or unidenti.ed species infection, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
	•	Pneumocystis jiroveci pneumonia
	•	Progressive multifocal leukoencephalopathy
	•	Salmonella (nontyphoid) septicemia, recurrent
	•	Toxoplasmosis of the brain with onset at after 1 mo of age
	•	Wasting syndrome in the absence of a concurrent illness other than HIV infection that could explain the following .ndings: (1) persistent weight loss >10% of baseline; (2) downward crossing of at least 2 of the following percentile lines on the weight-for-age chart (e.g., 95th, 75th, 50th, 25th, 5th) in a child 1 yr of age or older; OR (3) <5th>30 days); OR (2) documented fever (for >30 days, intermittent or constant)

Modified from the Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. Official authorized addenda: Human immunodeficiency virus infection codes and official guidelines for coding and reporting ICD-9-CM.MMWR Recomm Rep 1994;43(RR- 12):1ndash;19.

Infections.

Approximately 20% of AIDS-defining illnesses in children are recurrent bacterial infections caused primarily by encapsulated organisms such as Streptococcus pneumoniae and Salmonella ( Table 3 ). Other pathogens, including Staphylococcus, Enterococcus, Pseudomonas aeruginosa, and Haemophilus influenzae, and other gram-positive and gram-negative organisms may also be seen. Most of these infections are the result of HIV-related disturbances in humoral immunity. The most common serious infections are bacteremia, sepsis, and bacterial pneumonia, accounting for >50% of infections in HIV-infected children. Meningitis, urinary tract infections, deep-seated abscesses, and bone/joint infection occur less frequently. Milder recurrent infections, such as otitis media, sinusitis, and skin and soft tissue infections, are very common and may be chronic with atypical presentations.

Opportunistic infections are generally seen in children with severe depression of the CD4 count. In adults, these infections usually represent reactivation of a latent infection acquired early in life. In contrast, young children generally have primary infection and, lacking prior immunity, often have a more fulminant course of disease. This principle is best illustrated by Pneumocystis carinii (jiroveci) pneumonia (PCP), the most common opportunistic infection in the pediatric population . The peak incidence of PCP occurs at age 3–6 mo, with the highest mortality rate in children <1>

TABLE 3 -- 1993 Revised Case Definition of AIDS-Defining Conditions for Adults and Adolescents 13 Years of Age and Older

Candidiasis of bronchi, trachea, or lungs

Candidiasis, esophageal

Cervical cancer, invasive

Coccidioidomycosis, disseminated or extrapulmonary

Cryptococcosis, extrapulmonary

Cryptosporidiosis, chronic intestinal (>1 mo duration)

Cytomegalovirus disease (other than liver, spleen, or nodes)

Cytomegalovirus retinitis (with loss of vision)

Encephalopathy, HIV related

Herpes simplex:chronic ulcer(s) (>1 mo duration) or bronchitis, pneumonitis, or esophagitis

Histoplasmosis, disseminated or extrapulmonary

Isosporiasis, chronic intestinal (>1 mo duration)

Kaposi sarcoma

Lymphoma, Burkitt (or equivalent term)

Lymphoma, immunoblastic (or equivalent term)

Lymphoma, primary or brain

Mycobacterium avium complex or Mycobacterium kansasii infection, disseminated or extrapulmonary

Mycobacterium tuberculosis infection, any site, pulmonary or extrapulmonary

Mycobacterium, other species or unidentified species infection, disseminated or extrapulmonary

Pneumocystic jiroveci pneumonia

Pneumonia, recurrent

Progressive multifocal leukoencephalopathy

Salmonella septicemia, recurrent

Toxoplasmosis of brain

Wasting syndrome attributable to HIV

CD4+ T-lymphocyte count <200/μ>

Modified from the Centers for Disease Control and Prevention. 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992;41(RR-17):1–19.

Red Book: 2006 Report of the Committee on Infectious Disease, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2006, p 379.

The classic clinical presentation of PCP includes acute onset of fever, tachypnea, dyspnea, and marked hypoxemia; in some children, more indolent development of hypoxemia may precede other clinical or x-ray manifestations. Chest x-ray findings most commonly consist of interstitial infiltrates or diffuse alveolar disease, which rapidly progresses. Nodular lesions, streaky or lobar infiltrates, or pleural effusions may occasionally be seen. Diagnosis is established by demonstration of P. carinii (jiroveci) with appropriate staining of bronchoalveolar fluid lavage; rarely, an open lung biopsy is necessary.

The 1st line therapy for PCP is intravenous trimethoprim-sulfamethoxazole (TMP-SMZ) (15–20 mg/kg/day of TMP and 75–100 mg/kg/day of SMZ every 6 hr IV) with adjunctive corticosteroids if the Pao2 is <70>

Central Nervous System.

The incidence of CNS involvement in perinatally infected children is 50–90% in developing countries but lower in developed countries, with a median onset at 19 mo of age. This may range from subtle developmental delay to progressive encephalopathy with loss or plateau of developmental milestones, cognitive deterioration, impaired brain growth resulting in acquired microcephaly, and symmetric motor dysfunction. Encephalopathy may be the initial manifestation of the disease or may present much later when severe immune suppression occurs. With progression, marked apathy, spasticity, hyperreflexia, and gait disturbance may occur, as well as loss of language, oral, fine, and/or gross motor skills. The encephalopathy may progress intermittently, with periods of deterioration followed by transiently stable plateaus. Older children may exhibit behavioral problems and learning disabilities. Associated abnormalities identified by neuroimaging techniques include cerebral atrophy in up to 85% of children with neurologic symptoms, increased ventricular size, basal ganglia calcifications, and, less frequently, leukomalacia.

Focal neurologic signs and seizures are unusual and may imply a comorbid pathologic process such as a CNS tumor, opportunistic infection, or stroke. CNS lymphoma may present with a new onset of focal neurologic findings, headache, seizures, and mental status changes. Characteristic findings on neuroimaging studies include a hyperdense or isodense mass with variable contrast enhancement or a diffusely infiltrating contrast-enhancing mass. CNS toxoplasmosis is exceedingly rare in young infants, but may occur in HIV-infected adolescents; the overwhelming majority of these cases have the presence of serum IgG antitoxoplasma as a marker of infection. Other opportunistic infections of the CNS are rare and include CMV, JC virus (progressive multifocal leukoencephalopathy), HSV, and Cryptococcus or Coccidioides meningitis. Although the true incidence of cerebrovascular disorders (both hemorrhagic and nonhemorrhagic strokes) is unclear, 6–10% of children from large clinical series have been affected.

Respiratory Tract.

Recurrent upper respiratory tract infections such as otitis media and sinusitis are very common. Although the typical pathogens (S. pneumoniae, H. influenzae, Moraxella catarrhalis) are most common, unusual pathogens, such as P. aeruginosa, yeast, and anaerobes may be present in chronic infections and result in complications such as invasive sinusitis and mastoiditis.

LIP is the most common chronic lower respiratory tract abnormality, historically occurring in approximately 25% of HIV-infected children. LIP is a chronic process with nodular lymphoid hyperplasia in the bronchial and bronchiolar epithelium, often leading to progressive alveolar capillary block over months to years. It has a characteristic chronic diffuse reticulonodular pattern on chest radiography rarely accompanied by hilar lymphadenopathy, which allows a presumptive diagnosis to be made radiographically before the onset of symptoms. There is an insidious onset of tachypnea, cough, and mild to moderate hypoxemia with normal auscultatory findings or minimal rales. Progressive disease may be accompanied by digital clubbing and symptomatic hypoxemia, which usually resolves with oral corticosteroid therapy. Several studies suggest that LIP is associated with a primary Epstein-Barr virus infection in the setting of HIV infection.

Most symptomatic HIV-infected children experience at least 1 episode of pneumonia during the course of their disease. S. pneumoniae is the most common bacterial pathogen, but gram-negative bacteria may also be problematic; P. aeruginosa pneumonia occurs more commonly in severely symptomatic children (CDC C3 category) and is often associated with acute respiratory failure and death. Rarely, bronchiectasis can develop and cause recurrent secondary infections. PCP is the most common opportunistic infection, but other pathogens, including CMV, Aspergillus, Histoplasma, and Cryptococcus, can cause pulmonary disease. Infection with common respiratory viruses, including respiratory syncytial virus, parainfluenza, influenza, and adenovirus, may occur simultaneously and have a protracted course and period of viral shedding from the respiratory tract. Pulmonary and extrapulmonary tuberculosis has been reported with increasing frequency in HIV-infected children, although it is considerably more common in HIV-infected adults.

Cardiovascular System.

Subclinical cardiac abnormalities in HIV-infected children are common, persistent, and often progressive. A prospective study of young children with symptomatic HIV infection revealed that dilated cardiomyopathy and left ventricular hypertrophy were common; the 2 yr cumulative incidence of congestive heart failure was almost 5%. Children with encephalopathy or other AIDS-defining conditions have the highest rate of adverse cardiac outcomes. Resting sinus tachycardia has been reported in up to 64% and marked sinus arrhythmia in 17% of HIV-infected children. Hemodynamic instability occurs more frequently with advanced HIV disease. Gallop rhythm with tachypnea and hepatosplenomegaly appear to be the best clinical indicators of congestive heart failure in HIV-infected children; anticongestive therapy is generally very effective, especially when initiated early. Electrocardiography and echocardiography are helpful in assessing cardiac function before the onset of clinical symptoms.

Gastrointestinal and Hepatobiliary Tract.

Oral manifestations of HIV disease include erythematous or pseudomembranous candidiasis, periodontal disease (e.g., ulcerative gingivitis or periodontitis), salivary gland disease (i.e., swelling, xerostomia), and rarely ulcerations or oral hairy leukoplakia and ulcerations. Gastrointestinal tract involvement is common in HIV-infected children. A variety of pathogens can cause gastrointestinal disease, including bacteria (Salmonella, Campylobacter, MAC), protozoa (Giardia, Cryptosporidium, Isospora, microsporidia), viruses (CMV, HSV, rotavirus), and fungi (Candida). MAC and the protozoal infections are most severe and protracted in patients with severe CD4 cell depletion. Infections may be localized or disseminated and affect any part of the gastrointestinal tract from the oropharynx to the rectum. Oral or esophageal ulcerations, either viral in origin or idiopathic, are painful and often interfere with eating. Lesions that have negative viral cultures may respond to thalidomide, which is currently investigational, or to short courses of prednisone. AIDS enteropathy, a syndrome of malabsorption with partial villous atrophy not associated with a specific pathogen, has been postulated to be a result of direct HIV infection of the gut. Disaccharide intolerance is common in HIV-infected children with chronic diarrhea.

The most common symptoms of gastrointestinal disease are chronic or recurrent diarrhea with malabsorption, abdominal pain, dysphagia, and failure to thrive (FTT). Prompt recognition of weight loss or poor growth velocity in the absence of diarrhea is critical. Linear growth impairment often correlates with the level of HIV viremia. Supplemental enteral feedings should be instituted, either by mouth or with nighttime nasogastric tube feedings in cases associated with more chronic growth problems; placement of a gastrostomy tube for nutritional supplementation may be necessary. The wasting syndrome, defined as a loss of >10% of body weight, is not as common as FTT in pediatric patients. The resulting malnutrition is associated with a grave prognosis and generally requires parenteral hyperalimentation.

Chronic liver inflammation evidenced by fluctuating serum levels of transaminases with or without cholestasis is relatively common, often without identification of an etiologic agent. Cryptosporidial cholecystitis is associated with abdominal pain, jaundice, and elevated gamma GT. In some patients, chronic hepatitis caused by CMV, hepatitis B or C, or MAC may lead to portal hypertension and liver failure. Several of the anti-retroviral drugs or other drugs such as didanosine, protease inhibitors, and dapsone may also cause reversible elevation of transaminases.

Pancreatitis with increased pancreatic enzymes with or without abdominal pain, vomiting, and fever may be the result of drug therapy (e.g., with pentamidine, didanosine, or lamivudine) or, rarely, opportunistic infections such as MAC or CMV.

Renal Disease.

Nephropathy is an unusual presenting symptom of HIV infection, more commonly occurring in older symptomatic children. A direct effect of HIV on renal epithelial cells has been suggested as the cause, but immune complexes, hyperviscosity of the blood (secondary to hyperglobulinemia), and nephrotoxic drugs are other possible factors. A wide range of histologic abnormalities has been reported, including focal glomeru losclerosis, mesangial hyperplasia, segmental necrotizing glomerulonephritis, and minimal change disease. Focal glomerulosclerosis generally progresses to renal failure within 6–12 mo, but other histologic abnormalities in children may remain stable without significant renal insufficiency for prolonged periods. Nephrotic syndrome is the most common manifestation of pediatric renal disease, with edema, hypoalbuminemia, proteinuria, and azotemia with normal blood pressure. Cases resistant to steroid therapy may benefit from cyclosporine therapy. Polyuria, oliguria, and hematuria have also been observed in some patients.

Skin Manifestations.

Many cutaneous manifestations seen in HIV-infected children are inflammatory or infectious disorders that are not unique to HIV infection. These disorders tend to be more disseminated and respond less consistently to conventional therapy than in the uninfected child. Seborrheic dermatitis or eczema that is severe and unresponsive to treatment may be an early nonspecific sign of HIV infection. Recurrent or chronic episodes of HSV, herpes zoster, molluscum contagiosum, flat warts, anogenital warts, and candidal infections are common and may be difficult to control.

Allergic drug eruptions are also common, in particular related to sulfonamides, and generally respond to withdrawal of the drug or to desensitization. Epidermal hyperkeratosis with dry, scaling skin is frequently observed, and sparse hair or hair loss may be seen in the later stages of the disease.

Hematologic and Malignant Diseases.

Anemia occurs in 20–70% of HIV-infected children, more commonly in children with AIDS. The anemia may be due to chronic infection, poor nutrition, autoimmune factors, virus-associated conditions (hemophagocytic syndrome, parvovirus B19 red cell aplasia), or the adverse effect of drugs (zidovudine). In children with low erythropoietin levels, subcutaneous recombinant erythropoietin may be successful in treating the anemia.

Leukopenia occurs in almost ⅓ of untreated HIV-infected children, and neutropenia often occurs. In some cases, antineutrophil antibodies are the cause, and treatment with intravenous immunoglobulin (IVIG) has been successful. Multiple drugs used for treatment or prophylaxis for opportunistic infections such as PCP, MAC, and CMV or anti-retroviral drugs (zidovudine) may also cause leukopenia and/or neutropenia. In many cases, treatment with subcutaneous granulocyte colony-stimulating factor is successful.

Thrombocytopenia has been reported in 10–20% of patients. The etiology may be immunologic (i.e., circulating immune complexes or antiplatelet antibodies), or due to drug toxicity, or the cause may be unknown. Treatment with IVIG or anti-D offers temporary improvement in most cases. If ineffective, a 2–3 day course of high-dose steroids (30 mg/kg/day) may be an alternative. Anti-retroviral therapy may also reverse thrombocytopenia. Deficiency of clotting factors (factors II, VII, IX) is not rare in children with advanced HIV disease and is often easy to correct (vitamin K). A novel disease of the thymus has been observed in a few HIV-infected children. These patients were found to have characteristic anterior mediastinal multilocular thymic cysts without clinical symptoms. Histologic examination shows focal cystic changes, follicular hyperplasia, and diffuse plasmocytosis and multinucleated giant cells. Spontaneous involution occurred in some cases.

In contrast to the more frequent occurrence in adults, malignant diseases have been reported infrequently in HIV-infected children, representing only 2% of AIDS-defining illnesses. Non-Hodgkin lymphoma, primary CNS lymphoma, and leiomyosarcoma are the most commonly reported neoplasms among HIV-infected children. Epstein-Barr virus is associated with most lymphomas and with all leiomyosarcomas. Kaposi sarcoma, which is caused by human herpesvirus 8, occurs frequently among HIV-infected adults but is exceedingly uncommon among HIV-infected children.

DIAGNOSIS.

All infants born to HIV-infected mothers test antibody-positive at birth because of passive transfer of maternal HIV antibody across the placenta during gestation. Most uninfected infants lose maternal antibody between 6 and 12 mo of age and are known as seroreverters. Because a small proportion of uninfected infants continues to test HIV antibody positive for up to 18 mo of age, positive IgG antibody tests, including the rapid tests, cannot be used to make a definitive diagnosis of HIV infection in infants younger than this age. The presence of IgA or IgM anti-HIV in the infant's circulation can indicate HIV infection, because these immunoglobulin classes do not cross the placenta; however, IgA and IgM anti-HIV assays have been both insensitive and nonspecific and therefore are not valuable for clinical use. In any child >18 mo of age, demonstration of IgG antibody to HIV by a repeatedly reactive enzyme immunoassay (EIA) and confirmatory test (immunoblot or immunofluorescence assay) establishes the diagnosis of HIV infection.

Several rapid HIV tests are currently available with sensitivity and specificity better than those of the standard EIA. Many of these new tests require only a single step that allows test results to be reported within less than an hour. Incorporating rapid HIV testing during delivery or immediately after birth is crucial for the care of HIV-exposed newborns whose HIV status was unknown during pregnancy. Viral diagnostic assays, such as HIV DNA or RNA PCR, HIV culture, or HIV p24 antigen immune-dissociated p24 (ICD-p24), are considerably more useful in young infants, allowing a definitive diagnosis in most infected infants by 1–6 mo of age ( Table 4 ). By 4–6 mo of age, the HIV culture and/or PCR identify all infected infants. HIV DNA PCR is the preferred virologic assay in developed countries. Almost 40% of infected newborns have positive test results in the 1st 2 days of life, with >90% testing positive by 2 wk of age. Plasma HIV RNA assays, which detect viral replication, may be more sensitive than DNA PCR for early diagnosis, but data are limited. HIV culture has similar sensitivity to HIV DNA PCR; however, it is more technically complex and expensive, and results are often not available for several weeks compared with 2–3 days for PCR. The p24 antigen assay is also highly specific and easy to perform, but it is less sensitive than the other virologic tests. It is not recommended for diagnosis of infection in infants

TABLE 4 -- Laboratory Diagnosis of HIV Infection

TEST	COMMENT
HIV DNA PCR	Preferred test to diagnose HIV-1 subtype B infection in infants and children younger than 18 mo of age;highly sensitive and specific by 2 wk of age and available;performed on peripheral blood mononuclear cells. False negatives can occur in non-B subtype HIV-1 infections
HIV p24 Ag	Less sensitive, false-positive results during 1 mo of life, variable results;not recommended
ICD p24 Ag	Negative test result does not rule out infection;not recommended
HIV culture	Expensive, not easily available, requires up to 4 wk to do test;not recommended
HIV RNA PCR	Not recommended for routine testing of infants and children younger than 18 mo of age, because a negative result cannot be used to exclude HIV infection definitively. Preferred test to identify non-B subtype HIV-1 infections.

Red Book:2006 Report of the Committee on Infectious Diseases, 27th ed. Elk Grove Village, IL, American Academy of Pediatrics, 2006, p 386.

Ag, antigen;ICD, immune complex dissociated;PCR, polymerase chain reaction.

Viral diagnostic testing should be performed within the 1st 48 hr of life. Almost 40% of HIV-infected children can be identified at this time. It seems that many of these children have a more rapid progression of their disease and deserve more aggressive therapy. In exposed children with negative virologic testing at 2 days of life, additional testing should be done at 1–2 mo of age and at 4–6 mo of age; some also favor testing at age 14 days to maximize early detection of infected infants, if initiation of anti-retroviral therapy is desired. A positive virologic assay (i.e., detection of HIV by PCR, culture, or p24 antigen) suggests HIV infection and should be confirmed by a repeat test on a 2nd specimen as soon as possible. A diagnosis of HIV infection can be made with 2 positive virologic test results obtained from different blood samples.

Although the perinatal use of prophylactic zidovudine to prevent vertical transmission has not affected the predictive value of viral diagnostic testing, the effect of more intensive antiviral combinations (protease inhibitors) in pregnant women on the accuracy of the infant's viral tests is unknown. HIV infection can be reasonably excluded if an infant has had at least 2 negative virologic test results with at least 1 test performed at ≥4 mo of age. In some parts of the world where non-subtype B (the predominant type in the United States) are common, interpretation of a negative PCR test result should be done cautiously because the assay may not detect the particular subtype (group O). Close clinical monitoring with serologic testing (by 18 mo of age) or culture (if possible) is recommended. In older infants, 2 or more negative HIV antibody tests performed at least 1 mo apart past 6 mo of age in the absence of hypogammaglobulinemia or clinical evidence of HIV disease can reasonably exclude HIV infection. The infection can be excluded definitively if the same parameters are met when the infant is at least 18 mo of age.

Infants born to HIV-infected mothers should be prescribed zidovudine (ZDV) prophylaxis. A complete blood count, differential leukocyte count, and platelet count should be performed at 4 wk of age to monitor ZDV toxicity. If the child is found to be HIV-infected or if the HIV status is not clear, these tests should be continued every 1–3 mo to assess the hematologic effect of the disease or its treatment (prophylactic TMP-SMZ and anti-retroviral therapy). If the child is found to be HIV infected, CD4 and CD8 lymphocyte counts should be performed at 1 and 3 mo of age and repeated every 3 mo. The frequency of the test should be increased (every 4–6 wk) if the CD4 lymphocyte count or percentage declines rapidly.

TREATMENT.

The currently available therapy does not eradicate the virus and cure the patient; it only suppresses the virus for extended periods of time and changes the course of the disease to a chronic process. Decisions about anti-retroviral therapy for pediatric HIV-infected patients are based on the magnitude of viral replication (viral load), CD4 lymphocyte count or percentage, and clinical condition. Because anti-retroviral therapy changes as new drugs become available, decisions regarding therapy should be made in consultation with an expert in pediatric HIV infection. Plasma viral load monitoring and measurement of CD4 values have made it possible to implement rational treatment strategies for viral suppression as well as to assess the efficacy of a particular drug combination. The following principles form the basis for anti-retroviral treatment: (1) uninterrupted HIV replication causes destruction of the immune system and progression to AIDS; (2) the magnitude of the viral load predicts the rate of disease progression, and the CD4 cell count reflects the risk of opportunistic infections and HIV infection complications; (3) combinations of HAART, which include at least 3 drugs, should be the initial treatment. Potent combination therapy that suppresses HIV replication to an undetectable level restricts the selection of anti-retroviral-resistant mutants; drug-resistant strains are the major factor limiting successful viral suppression and delay of disease progression; (4) the goal of sustainable suppression of HIV replication is best achieved by the simultaneous initiation of combinations of anti-retroviral agents to which the patient has not been exposed previously and which are not cross-resistant to drugs with which the patient has been treated previously; (5) adherence to the complex drug regimens is crucial for a successful outcome.

Combination Therapy.

Anti-retroviral drugs licensed as of 2006 are categorized by their mechanism of action, such as the ability to inhibit the HIV reverse transcriptase or protease enzymes ( Table 5 ). Within the reverse transcriptase inhibitors, a further subdivision can be made: nucleoside (or nucleotide) reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). The NRTIs have a similar structure to the building blocks of DNA (e.g., thymidine, cytosine). When incorporated into DNA, they act like chain terminators and block further incorporation of nucleosides, which prevents viral DNA synthesis. Among the NRTIs, thymidine analogs (stavudine [d4T], zidovudine [ZDV]) are found in higher concentrations in activated or dividing cells, and nonthymidine analogs (didanosine [ddI], lamivudine [3TC]) have more activity in resting cells. Activated cells are thought to produce >99% of the population of HIV virons. In contrast, resting cells account for 1%

TABLE 5 -- Summary of Anti-retroviral Therapies (available in 2006)

DRUG (TRADE NAMES, FORMULATIONS)

DOSING

SIDE EFFECTS

COMMENTS

NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIS)

Class adverse effects:Lactic acidosis with hepatic steatosis

Abacavir

	Ziagen, ABC
	Tablet:300 mg
	Oral solution:20 mg/mL

-	Children: ≥3 mo to 18 yr:8 mg/kg PO bid (maximum dose 300 mg PO bid)
-	Adults:300 mg PO bid or 600 mg PO once daily

-	Common:Nausea, vomiting, anorexia, fever, headache, diarrhea, rash
-	Less common:Hypersensitivity, lactic acidosis with hepatic steatosis, hepatomegaly, pancreatitis, elevated triglycerides, fatigue

Can be given with food.Serious hypersensitivity reaction occurs rarely;if hypersensitivity is suspected, do not rechallenge.

Didanosine

-	Videx, ddI
	Chewable buffered tablet:25, 50, 100, 150, 200 mg
	Buffered powder packet:100, 167, 250 mg

Infants 2 wk to 8 mo:50–100 mg/m 2 PO bid

Children:120 mg/m2 (range 90–150 g/m 2) PO bid

Adolescents (>13 yr) and adults <60 st="on">PO bid)

>60 kg:200 mg PO bid (buffered oral solution 250 mg PO bid)

-	Common: Headache, diarrhea, abdominal pain, nausea, vomiting.
-	Less common: Pancreatitis, peripheral neuropathy, electrolyte abnormalities, lactic acidosis with hepatic steatosis, hepatomegaly, retinal depigmentation

-	Food decreases bioavailability up to 50%.Tablets dissolved in water are stable for 1 hr (4 hr in buffered solution).
-	Drug interactions: Antacids/gastric acid antagonists may increase bioavailability;possible decreased absorption of fluoroquinolones, ganciclovir, ketoconazole, itraconazole, dapsone.Possible decreased efficacy when given with tenofovir.

Videx EC

Capsule, delayed release:125, 200, 250, 400 mg

-	Children:Not established
-	Adolescent and adults: <60 st="on">PO once daily ≥60 kg:400 mg PO once daily

Same as for ddI

Combination with tenofovir increases ddI levels and risk for toxicity.Swallow capsules whole on empty stomach, 30 min before meals or 2 hr after meals

Emtricitabine

	Emtriva, FTC
	Capsules:200 mg
	Oral solution:10 mg/mL

Children ≥33 kg, adolescents and adults:200 mg capsule PO once daily or 240 mg (24 mL) oral solution q.d.

	Common: Headache, diarrhea, nausea, skin discoloration
	Less common:Lactic acidosis with hepatic steatosis, hepatomegaly

Closely monitor patients with hepatitis B co-infection. Can be given with food.

Lamivudine

	Epivir, Epivir HBV, 3TC
	Tablet:150, 300 mg
	Solution:5 mg/mL (Epivir HBV, 10 mg/mL)

Infants, neonates <30 days: 2 mg/kg PO bid

Infants, children and adolescents:4 mg/kg PO bid (maximum dose:150 mg PO bid)

Adults:

<50 st="on">PO bid)

≥50 kg:150 mg PO bid

300 mg PO once daily

-	Common: Headache, nausea, feeding problems, diarrhea, abdominal pain, rash
-	Less common: Pancreatitis, neutropenia, peripheral neuropathy, lactic acidosis with hepatic steatosis, hepatomegaly

-	May be administered with or without food.
-	Drug interactions: Trimethoprim/sulfamethoxazole increases 3TC levels.Combination with ZDV may prevent ZDV resistance.

Stavudine

	Zerit, d4T
	Capsule:15, 20, 30, 40 mg
	Solution:1 mg/mL

Children <30 st="on">PO bid.

Adolescents and adults:

30–60 kg:30 mg PO bid

>60 kg:40 mg PO bid

-	Common: Headache, nausea, rash
-	Less common: Peripheral neuropathy, pancreatitis, lactic acidosis with hepatic steatosis, hepatomegaly, elevated liver function tests

Drug interactions:Can be given with food.Should not be administered with ZDV.

Zerit XR

Capsule:75, 100 mg

	<60 st="on">PO once daily
	>60 mg kg:100 mg PO once daily

Tenofovir

	Viread, TDF
	Tablet:300 mg

-	Children:Not established
-	Adolescents and adults:300 mg PO once daily

-	Common: Nausea, vomiting, diarrhea
-	Less common: Lactic acidosis with hepatic steatosis, hepatomegaly, reduced bone density

High fat meal increases absorption.Co-administration with ddI may increase ddI toxicity.Co-administration with atazanavir (ATV) may decrease ATV levels. Boosting with ritonavir (RTV) is required.

Zidovudine

	Retrovir, AZT, ZDV
	Capsule:100 mg
	Tablet:300 mg
	Syrup:10 mg/mL
	Injection:10 mg/mL

	Prophylaxis (newborns)
-	Term neonates: 2 mg/kg PO every 6 hr or 2.7 mg/kg PO every 8 hr or 1.5 mg/kg/dose IV every 6 hr (infuse over 30 min)
-	Premature infants (<30> 1.5 mg/kg IV every 12 hr or 2 mg/kg PO every 12 hr for age 0–4 wk, then every 8 hr
-	Premature infants (≥30 wk gestation): 1.5 mg/kg/dose IV every 12 hr or 2 mg/kg PO every 12 hr for age 0–2 wk, then every 8 hr
-	Treatment Children 6 wk to 12 yr: 160 mg/m2 PO every 8 hr or 180–240 mg/m 2 PO every 12 hr or 120 mg/m2 IV every 6 hr or Continuous infusion 20 mg/m2/hr IV
-	Adolescents and adults:200 mg PO tid or 300 mg PO bid

-	Common: Headache, bone marrow suppression (e.g., anemia, leukopenia)
-	Less common: Liver toxicity, lactic acidosis with hepatic steatosis, myopathy, hepatomegaly

Can be given with food.Infuse IV with 5% dextrose over 1 hr at a final concentration of 4 mg/mL.

Drug interactions: Rifampin may increase metabolism

Cimetidine, fluconazole, valproic acid may decrease metabolism.

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS)

Class adverse effects:Rash—mild to severe, usually within first 6 wk.Discontinue the drug if severe rash (with blistering, desquamation, muscle involvement or fever)

Efavirenz

	Sustiva, EFV
	Capsule:50, 100, 200 mg
	Tablet:600 mg

-	Children <3>
-	Children ≥3 yr: Given once daily PO at bedtime Weight 10– <15>

-	Adolescents and adults:600 mg once daily PO at bedtime

-	Common: Rash, CNS and psychiatric symptoms (e.g., abnormal dreams, impaired concentration, insomnia, depression, hallucination)
-	Less common: Increased liver enzymes;potentially teratogenic

Capsules can be opened for mixing in food.Do not administer with fatty foods because absorption is increased 50%, but may administer with regular meals or without food.

Drug interactions: Efavirenz induces CYP3A4 and may increase clearance of drugs metabolized by this pathway (e.g., antihistamines, sedative and hypnotics, cisapride, ergot derivatives, warfarin, ethinyl estradiol) and several other ARVs (i.e., protease inhibitors).Drugs that induce CYP3A4 (e.g., henobarbital, rifampin, rifabutin) decrease efavirenz levels.Clarithromycin levels decrease with EFV and azithromycin should be considered.

Nevirapine

	Viramune, NVP
	Tablet:200 mg
	Suspension:10 mg/mL

-	Neonates 0–2 mo:5 mg/kg or 120 mg/m 2 PO once daily for 14 days, then 120 mg/m2 PO bid for 14 days, then 200 mg/m2 PO bid.
-	Children 2 mo–8 yr:4 mg/kg PO once daily for 14 days; if tolerated, increase dose to 7 mg/kg PO bid (maximum dose 200 mg PO bid) ≥8 yr:4 mg/kg PO once daily for 14 days;if tolerated, increase dose to 4 mg/kg PO bid (maximum dose 200 mg PO bid)

-	Adolescents and adults:200 mg once daily for 14 days; if tolerated, increase dose to 200 mg PO bid

-	Common: Rash (can be severe, including Stevens-Johnson syndrome), headache, fever, nausea, abnormal liver function tests
-	Less common: Hepatitis (rarely life threatening), hypersensitivity reactions

May give with or without food.

Drug interactions: Induces hepatic CYP450 3A activity and decreases protease inhibitors concentrations such as indinavir, s aquinavir, and lopinavir concentrations. Also reduces ketoconazole concentrations (fluconazole should be used as an alternative). Rifampin decreases nevirapine serum levels. Anticonvulsants and psychotropic drugs using same metabolic pathways as NVP should be monitored. Oral contraceptives may also be affected.

PROTEASE INHIBITORS

Class adverse effects:Hyperglycemia, hyperlipidemia (except atazanavir), lipodystrophy, increased transaminases, increased bleeding disorders in hemophiliacs.Can induce metabolism of ethinyl estradiol;use alternate contraception (other than estrogen-containing oral contraceptives).All undergo hepatic metabolism, mostly by CPY3A4, with many drug interactions!

Amprenavir

	Agenerase, APV
	Liquid formulation:15 mg/mL
	Capsules:50 mg

-	Neonates/infants:Not recommended due to propylene glycol
-	Children 4–16 yr and weighing <50> Oral solution 22.5 mg/kg PO bid; >50 kg: 1,400 mg/dose PO bid;(maximum daily dose: 2,800 mg)

-	Adolescents 13–16 yr and >5 kg, and adults:Use fosamprenavir (fos-APV) rather than APV
-	Adult dose in combination with ritonavir: APV 600 mg + 100 mg RTV PO bid

-	Common: Vomiting, nausea, diarrhea, rash
-	Less common: Stevens-Johnson syndrome, fat redistribution, insulin resistance

Liquid formulation contains vitamin E;supplemental vitamin E should not be given.Do not use liquid formulation <4>

Atazanavir

	Reyataz, ATV
	Capsules:100, 150, 200 mg

Children:Not established

Adolescents/adults:

Antiretroviral naive:

400 mg PO once daily

Antiretroviral experienced:

ATV 300 mg + RTV 100 mg PO once daily

-	Common:Asymptomatic elevation of indirect bilirubin; headache, arthralgia, depression, insomnia, nausea, vomiting, diarrhea, paresthesias
-	Less common: Prolongation of PR interval on ECG;rash, rarely progressing to Stevens-Johnson syndrome

Review drug interactions before initiating because ATV interacts with drugs using CYP3A4 for metabolism. Use with caution with cardiac conduction disease or liver impairment

Darunavir

Prezista, DRV

-	Limited data on pediatric dosing or safety
-	Adults 600 mg DRV PO + 100 mg RTV, bid

-	Common:Diarrhea, nausea, abdominal pain, fatigue, headache
-	Less common:Skin rash including erythema multiforme and Stevens-Johnson syndrome, lipid elevations

-	Contraindicated for concurrent therapy with cisapride, ergot alkaloids, benzodiazepines, pimozide or any major CYP3A4 substrates.Use with caution in patients taking anticonvulsants, strong CYP3A4 inhibitors, or moderate/ strong CYP3A4 inducers.Adjust dose with concurrent rifamycin therapy.
-	Contains sulfa:potential for cross-sensitivity with sulfonamide class is unknown.

Fosamprenavir

	Lexiva, fos-APV
	Tablets:700 mg

Children:Not established

Adolescent/adults:

Antiretroviral naive:

fos-APV 1,400 mg PO bid

fos-APV 1,400 mg + RTV 200 mg RTV PO once daily

fos-APV 700 mg + RTV 100 mg PO bid

Protease inhibitor-experienced:

fos-APV 700 mg + RTV 100 mg RTV PO bid

-	Common: Nausea, vomiting, perioral paresthesias, headache, rash, lipid elevations
-	Less common: Stevens-Johnson syndrome, fat redistribution, neutropenia, elevated creatine kinase
-	Rare: Diabetes mellitus

Use with caution in sulfa-allergic individuals.Interacts with drugs utilizing CYP3A4 metabolism.

Indinavir

	Crixivan, IDV
	Capsule:100, 200, 333, 400 mg

-	Infants: Not approved
-	Children: Dose not established Investigational dose: 500 mg/m2 every 8 hr (max single dose:800 mg)
-	Adolescent and Adults 800 mg every 8 hr (not tid)
	Boosted PID dosing:IDV 800 mg + 100–200 RTV bid Dosing with NNRTIs:IDV 1,000 mg PO every 8 hr + EFV or NVP;or IDV 800 mg + RTV 200 mg PO bid with EFV or NVP

-	Common: Nausea, hyperbilirubinemia, headache, dizziness, lipid abnormalities
-	Less common: Nephrolithiasis, interstitial nephritis, fat redistribution
-	Rare:Diabetes mellitus, hepatitis

Administer on an empty stomach 1 hr before or 2 hr after a meal to decrease food effect.When co-administered with boosting dose of ritonavir, no food restrictions. Reduce dose by ∼25% with mild to moderate liver dysfunction.Adequate hydration (48 oz fluid/day in adults) necessary to minimize risk of nephrolithiasis. Chemoprophylaxis is after high-risk exposure given in combination with zidovudine and lamivudine.

Drug interactions:Didanosine decreases absorption; rifampin reduces levels;ketoconazole, ritonavir, and other protease inhibitors decrease indinavir metabolism. Do not co-administer astemizole, cisapride, terfenadine.

Lopinavir/Ritonavir (co-formulated)

	Kaletra, LPV/RTV, LPV/r
	Capsules:133.3 mg LPV/33.3 mg RTV
	Oral solution:80 mg LPV-20 mg
	RTV/mL (contains 42% alcohol by volume)

-	Infants <6>
-	Children: 7– <15 st="on">PO bid 15–40 kg:10 mg LPV and 2.5 mg RTV/kg PO bid >40 kg:400 mg LPV and 100 mg RTV/kg PO bid or 230 mg and LPV-57.5 mg RTV/m2 PO bid (maximum 400 mg LPV and 100 mg RTV/dose)


-	Adolescents and adults: 400 mg LPV and 100 mg RTV PO bid

-	More common: Diarrhea, headache, nausea and vomiting, lipid elevation
-	Less common: Fat redistribution
-	Rare: Diabetes mellitus, pancreatitis, hepatitis

Adjust dose when used with NNRTIs and other protease inhibitors;interacts with drugs using CYP3A4

Nelfinavir

	Viracept, NFV
	Tablet:250, 625 mg
	Powder for suspension:50 mg/level scoop of powder

-	Neonates:Investigational dose 10 mg/kg every 8 hr; not recommended for children <2>
-	Children 2–13 yr :45–55 mg/kg bid or 25–35 mg/kg tid
-	Adolescents and Adults:750 mg PO tid or 1,250 mg PO bid

-	Common: Diarrhea asthenia, abdominal pain, rash, lipid abnormalities
-	Less common: Exacerbation of liver disease, fat redistribution
-	Rare: Diabetes, hepatitis

-	Administer with a me al to optimize absorption;avoid acidic food or drink (e.g., orange juice).Tablet can be dissolved in water to administer as a solution.
-	Drug interactions: Nelfinavir inhibits CYP3A4 activity, which may cause multiple drug interactions.Rifampin, phenobarbital, and carbamazepine reduce levels. Ketoconazole, ritonavir, indinavir, and other protease inhibitors increase levels.Do not co-administer astemizole, cisapride, terfenadine.May interfere with oral contraceptives.

Ritonavir

-	Norvir, RTV
	Capsule:100 mg
	Solution:80 mg/mL

-	Children:200 mg/m2 every 12 hr;titrate upward in 50 mg/m2 dose increments (to increase tolerability) to 400 mg/m2 every 12 hr
-	Adolescents and adults:600 mg every 12 hr

-	Common:Nausea and vomiting, diarrhea, taste aversion, elevated serum lipids, perioral paresthesias
-	Less common:Fat redistribution
-	Rare:Pancreatitis, hepatitis, diabetes mellitus

-	Administer dose with food to enhance bioavailability
-	Drug interactions:Ritonavir is a substrate and has affinity for many hepatic CYP450 enzymes that may lead to many important drug interactions (e.g., protease inhibitors, antiarrhythmics, antidepressants, cisapride). Ritonavir metabolism is influenced by enzyme inducers and inhibitors.Ritonavir-resistant strains oftencross-resistant with other agents.

Saquinavir

-	Invirase, SQV
-	Hard gelatin capsule:200, 600 mg

-	Infants and children:Not established
-	≥16 yr:1,000 mg plus 100 mg RTV, both bid

-	Common:Diarrhea, abdominal pain, headache, nausea, rash, lipid abnormalities
-	Rare:Diabetes mellitus, pancreatitis, elevated transaminases

-	Administration with a high-fat meal enhances bioavailability.Concurrent grapefruit juice may increase bioavailability.Use only in combination with ritonavir boosting dose;lacks potency when given as single protease inhibitor.
-	Drug interactions:Rifampin, phenobarbital, and carbamazepine decrease serum levels;saquinavir may decrease metabolism of calcium channel antagonists; azoles (e.g., ketoconazole), macrolides, and ritonavir increase levels.

Tipranavir

-	Aptivus, TPV

-	Limited data on pediatric dosing or safety
-	Adults:500 mg TPV PO + 200 mg RTV PO, bid with a high-fat meal.

-	Common:Diarrhea, nausea, fatigue, headache, elevated liver enzymes, triglycerides and cholesterol
-	Less common:Fat redistribution, hepatic decompensation
-	Rare:Fatal and nonfatal intracranial hemorrhage have been reported, but causal relationship is not established

Can inhibit human platelet aggregation:use with caution in patients at risk for increased bleeding (trauma, surgery, etc.) or in patients receiving concurrent medications which may increase the risk of bleeding. Contraindicated in patients with hepatic insufficiency or receiving concurrent therapy with amiodarone, cisapride, ergot alkaloids, benzodiazepines, pimozide.

FUSION INHIBITORS

Enfuvirtide

-	Fuzeion
-	Injection:Lyophilized powder of 108 mg reconstituted in 1.1 sterile water delivers 90 mg/mL

-	Children <6>
-	Children >6 yr:2 mg/kg bid

-	Common:Local injection site reactions in 98%:erythema, induration nodules, cysts, ecchymoses
-	Less common:Increased incidence of bacterial pneumonia
-	Rare:Hypersensitivity including fever, chills, hypotension;immune-mediated reactions (e.g., glomerulonephritis, respiratory distress)

Give subcutaneously in the upper arm, anterior leg or abdomen (maximum:90 mg/dose).Severity of adverse effects increased if give intramuscularly Injection sites should be rotated

COMBINATION PRODUCTS

These combinations can be used in adolescents at appropriate Tanner stage (Tanner stages IV and V) and weight (>40 kg).

Atripla

Each tablet contains 600 mg Efavirenz, 200 mg emtricitabine, and 300 mg tenofovir disoproxil fumarate

Adult dose:1 tablet PO once daily

Combivir

Each tablet contains 300 mg AZT + 150 mg

3TC

Adult dose:1 tablet PO bid

Epzicom

Each tablet contains 300 mg 3TC + 600 mg

ABC

Adult dose:1 tablet PO once daily

Trizivir

Each tablet contains 300 mg AZT + 150 mg

3TC + 300 mg ABC

Adult dose:1 tablet PO bid

Truvada

Each tablet contains 200 mg FTC + 300 mg

TDF

Adult dose:1 tablet PO once daily

Antiretroviral drugs often have significant drug-drug interactions, with each other and with other classes of medicines, which sho uld be reviewed before initiating any new medication.

The information in this table is not all-inclusive. Updated and additional information on dosing, drug-drug interactions, and toxicities is available on the AIDSinfo website at http://www.aidsinfo.nih.gov. CNS, central nervous system.

While the principal site of viral replication is lymphoid tissue, sanctuary sites such as the CNS may harbor residual virions with the potential of being a source of local or persistent disease. Impaired penetration of drugs to these compartments could result in development of resistance. Although data on CNS penetration of antiviral agents are presently limited, ZDV, d4T, and 3TC appear to achieve inhibitory concentrations in the CNS. Indinavir and nevirapine also penetrate the CSF, but other protease inhibitors are actively transported out of the CNS, thereby limiting their potential efficacy at this site.

By targeting different points in the viral life cycle and stages of cell activation, and delivering drug to all tissue sites, maximal viral suppression may be feasible. Combinations of 3 drugs (thymidine analog NRTI [ZDV], a nonthymidine analog NRTI [3TC] to suppress replication in both active and resting cells, and a protease inhibitor [lopinavir/ritonavir or nelfinavir] or an NNRTI [efavirenz]) have been shown to produce prolonged viral suppression. Although not ideal, less potent combinations such as triple NRTIs (abacavir, zidovudine, lamivudine), dual NRTIs, or ritonavir with stavudine may be considered in special situations when there are concerns about adherence to a complex drug regimen or when the patient and/or family prefer a simplified alternative regimen. Combination treatment increases the rate of toxicities (see Table 5 ), and complex drug-drug interactions exist among many of the anti-retroviral drugs. Most NNRTI and protease inhibitor drugs are inducers or inhibitors of the cytochrome P450 system. The protease inhibitors are particularly likely to have serious interactions with multiple drug classes, including nonsedating antihistamines and psychotropic, vasoconstrictor, antimycobacterial, cardiovascular, analgesic, and gastrointestinal drugs (cisapride). Whenever new medications are added to an anti-retroviral treatment, especially a protease inhibitor–containing regimen, a pharmacist and/or HIV specialist should be consulted to address possible drug interactions. The inhibitory effect of ritonavir (a protease inhibitor) on the cytochrome P450 system has been exploited, and small doses of the drug are added to several other protease inhibitors (lopinavir, indinavir, saquinavir) to slow their metabolism by the P450 system and to improve their pharmacokinetic profile. This provides more effective drug levels with less toxicity and, often, less frequent dosing.

Adherence.

Assessment of the likelihood of adherence to treatment is an important factor in deciding whether and when to ini tiate therapy. Numerous studies have shown that compliance of <80–90%>
Initiation of Therapy.

HIV-infected children with symptoms (clinical category A, B, or C) or with evidence of immune dysfunction (immune category 2 or 3) should be treated with anti-retroviral therapy, regardless of age or viral load (see Tables 1 and 2 [1] [2]). Children <1>

Some clinicians advocate treating asymptomatic children ≥1 yr of age to prevent immunologic deterioration. When there are concerns regarding drug adherence, safety, and durability of anti-retroviral response, some providers elect to delay treatment in the immunologically normal child with a viral load of <100,000>

Inflammatory immune reconstitution syndromes have been described for children and adults, and represent the paradoxical emergence of transient to severe inflammation-mediated symptoms as immune function is restored with anti-retroviral therapy. Most of these syndromes are associated with mycobacterial infections, especially M. tuberculosis, and have also been reported with P. carinii, Toxoplasma, hepatitis B and hepatitis C viruses, CMV, and other pathogens. Immune reconstitution syndromes are characterized by fever and worsening of the clinical manifestations of the opportunistic infection or new manifestations, typically within the 1st few weeks after initiation of anti-retroviral therapy, although they may occur up to several months after the initiation. Determining whether the symptoms represent worsening of a current infection or a new opportunistic infection, an immune reconstitution syndrome, or drug toxicity is often very difficult. If the syndrome does represent an immune reactivation syndrome, adding nonsteroidal anti-inflammatory agents or corticosteroids to alleviate the inflammatory reaction is appropriate. The inflammation may take weeks or months to subside.
Dosing.

Data on anti-retroviral drug dosages for neonates are often limited. Because of the immaturity of the neonatal liver, premature infants and newborns often require an increase in the dosing interval of drugs primarily cleared through hepatic glucuronidation.

Adolescents should have anti-retroviral dosages prescribed on the basis of Tanner staging of puberty rather than on the basis of age. During early puberty (Tanner stages I, II, and III), pediatric dosing ranges should be used, whereas adolescents in late puberty (Tanner stages IV and V) should follow adult dosing schedules.
Changing Anti-Retroviral Therapy.

Therapy should be changed when the current regimen is judged ineffective as evidenced by increase in viral load, deterioration of the CD4 cell count, or clinical progression. Development of toxicity or intolerance to drugs is another reason to consider a change in therapy. When a change is considered, the patient and family should be reassessed for adherence problems. While considering possible new drug choices, potential cross-resistance should be addressed. In addition, few patients who have virologic failure may still demonstrate elevated CD4 cell counts (discordant response). Impaired replication ability of the resistant virus and enhanced cytotoxic T lymphocyte (CTL) effects are some of the reasons for this discordant response. In these patients, delay in changing therapy should be considered as long as the immunologic benefit is evident. Ideally, when a decision is made to change the anti-retroviral therapy, all drugs should be changed. However, in many situations (previous anti-retroviral experience, intolerance, toxicity) this is not possible, and, therefore, at least 2 drugs should be changed based on the resistance mutation genotype (if available) or previous regimen used.

Monitoring Anti-Retroviral Therapy.

Virologic and immunologic surveillance (using HIV RNA copy number and CD4 lymphocyte count or percentage) as well as clinical assessment should be performed regularly in children taking anti-retroviral therapy. Initial virologic response (i.e., at least 5-fold [0.7 log10] reduction in viral load) should be achieved within 4 wk of initiating anti-retroviral therapy. The maximum response to therapy usually occurs within 12–16 wk. Thus, HIV RNA levels should be measured at 4 wk and 3–4 mo after therapy initiation. Once an optimal response has occurred, viral load should then be measured at least every 3–6 mo. If the response is unsatisfactory, another viral load should be performed as soon as possible to verify the results before a change in therapy is considered. The CD4 cells respond more slowly to successful treatment and, therefore, can be monitored less frequently. Potential toxicity should be monitored closely for the 1st 8–12 wk, and if no clinical or laboratory toxicity is documented, a follow-up visit every 2–3 mo is adequate. Several toxicities have caused increasing concern regarding anti-retroviral use (especially protease inhibitors). These toxicities include hematologic complications, hypersensitivity rash, lipodystrophy (e.g., redistribution of body fat), hyperlipidemia (elevation of cholesterol and triglyceride concentrations), hyperglycemia and insulin resistance, mitochondrial toxicity leading to severe lactic acidosis, abnormal bone mineral metabolism, and hepatic toxicity including severe hepatomegaly with steatosis.

Resistance to Anti-Retroviral Therapy.

The high mutation rate of HIV (mainly due to the absence of error-correcting mechanisms) severely impairs the success of anti-retroviral therapy. Failure to reduce the viral load to <50>

Supportive Care.

Even before the new anti-retroviral drugs were available, a significant impact on the quality of life and survival of HIV-infected children was achieved when supportive care was given. A multidisciplinary team approach is desirable for successful management. Close attention should be paid to nutrition status, which is often delicately balanced and may require aggressive preemptive intervention (nasogastric or gastric feedings or parenteral nutrition) to achieve adequate caloric and protein intake. Painful oropharyngeal lesions and dental caries are frequent and may interfere with eating; routine dental evaluations and careful attention to oral hygiene should be encouraged. Development should be evaluated regularly with provision of necessary physical, occupational, and/or speech therapy. Recognition of pain in the young child may be difficult, and effective pharmacologic and nonpharmacologic protocols for pain management should be instituted, especially during the terminal phase of the disease.

All HIV-exposed and infected children should receive standard pediatric immunizations. In general, live oral polio vaccine and live bacterial vaccines (BCG) should not be given ( Fig. 2 ). Varicella and measles-mumps-rubella (MMR) vaccines are recommended for children in immune categories 1 and 2, but neither varicella nor MMR vaccines should be given to severely immunocompromised children (immune category 3). Of note, prior immunizations do not always provide protection, as evidenced by outbreaks of measles and pertussis in immunized HIV-infected children.

Figure 2 Differences in immunization schedule for HIV-infected children from the routine childhood immunization schedule

Prophylactic regimens are integral for the care of HIV-infected children. All infants between 6 wk and 1 yr of age who are proven to be HIV infected should receive prophylaxis regardless of the CD4 count or percentage (see Table 5 ). Infants exposed to HIV-infected mothers should receive the same prophylaxis until they are proven to be noninfected. When the HIV-infected child is >1 yr of age, prophylaxis should be given according to the CD4 lymphocyte count ( Table 6 ). The best prophylactic regimen is 150/750 mg/m2/day of TMP/SMZ given as 1–2 daily doses 3 days per week. If the patient experiences a mild allergic reaction (rash), desensitization is usually successful to allow daily TMP/SMZ prophylaxis. For severe adverse reactions to TMP/SMZ, alternative therapies include dapsone, atovaquone, or pentamidine (aerosolized or intravenous).

TABLE 6 -- Recommendations for PCP Prophylaxis and CD4 Monitoring for HIV-Exposed Infants and HIV-Infected Children, by Age and HIV Infection Status

AGE/HIV INFECTION STATUS	PCP PROPHYLAXIS	CD4 MONITORING
Birth to 4–6 wk, HIV exposed	No prophylaxis	1 mo
4–6 wk to 4 mo or HIV exposed 4–12 mo	Prophylaxis	3 mo
HIV-infected or indeterminate	Prophylaxis	6,9, and 12 mo
HIV infection reasonably excluded^[*]	No prophylaxis	None
1–5 yr, HIV infected	Prophylaxis if:	Every 3–4 mo^[†]
	CD4 count is <500>
6–12 yr, HIV infected	Prophylaxis if:	Every 3–4 mo^[‡]
	CD4 count is <200>[§]

HIV infection can be reasonably excluded among children who have had 2 or more negative HIV diagnostic tests (i.e., HIV culture or polymerase chain reaction), both of which are performed at ≥1 mo of age and one of which is performed at ≥4 mo of age, or 2 or more negative HIV IgG antibody tests performed at >6 mo of age among children who have no clinical evidence of HIV disease. † More frequent monitoring (e.g., monthly) is recommended for children whose CD4 counts or percentages are approaching the threshold at which prophylaxis is recommended. ‡ Children 1–2 yr of age who were receiving PCP prophylaxis and had a CD4 count of Prophylaxis against MAC should be offered to HIV-infected children with advanced immunosuppression (i.e., CD4 lymphocyte count <500>6 yr of age). The drugs of choice are clarithromycin (7.5 mg/kg bid PO) or azithromycin (20 mg/kg once a week PO or 5 mg/kg once daily PO).

Primary prophylaxis against opportunistic infections may be discontinued if patients have experienced sustained (>6 mo duration) immune reconstitution with HAART. Even if patients have had opportunistic infections such as PCP or disseminated MAC, it may also be possible to discontinue prophylaxis if immune reconstitution has been sustained.

Some experts recommend IVIG to prevent recurrent serious bacterial infections for symptomatic HIV-infected children who (1) have suffered from at least 2 documented serious bacterial infections within 1 yr, (2) have laboratory-documented inability to make antigen-specific antibodies, or (3) are hypogammaglobulinemic. The dose is 400 mg/kg every 4 wk.

All HIV-exposed children should have skin testing (5TU PPD) for tuberculosis at 1 yr of age and be retested every 2 yr. If the child is living in close contact with a person with tuberculosis, he or she should be tested more frequently. To reduce the incidence of other potential infections, parents should be counseled about (1) the importance of good handwashing, (2) avoiding raw or undercooked food (Salmonella), (3) avoiding drinking or swimming in lake or river water or being in contact with young farm animals (Cryptosporidium), and (4) the risk of playing with pets (Toxoplasma and Bartonella from cats, Salmonella from reptiles).

Because of the frequent changes in these guidelines, physicians providing care to few HIV-exposed or infected children should periodically consult physicians with expertise in pediatric HIV infection.

PROGNOSIS.

The improved understanding of the pathogenesis of HIV infection in children and the availability of more effective anti-retroviral drugs has changed the prognosis considerably. In developed countries where early diagnosis leads to prompt anti-retroviral therapy, progression of the disease to AIDS and the mortality rate have diminished. HIV-infected children live longer with improved quality of life. Even with only partial reduction of viral load, children may have both significant immunologic and clinical benefits. In general, the best prognostic indicators are the sustained suppression of plasma viral load and CD4+ lymphocytes. If determinations of viral load and CD4 lymphocytes are available, the results can be used to evaluate prognosis. It is unusual to see rapid progression in an infant with a viral load <100,000>100,000 copies/mL) over time is associated with greater risk for disease progression and death. CD4 lymphocyte percentage is another prognostic indicator, and the mortality rate is higher in patients with a CD4 lymphocyte percentage of <15%.>30% of such children dying before age 3 yr of age. In contrast, lymphadenopathy, splenomegaly, hepatomegaly, lymphoid interstitial pneumonitis, and parotitis are indicators of a better prognosis.

PREVENTION.

Interruption of perinatal transmission from mother-to-child has been achieved by administering ZDV chemoprophylaxis (200 mg every 8 hr) to the pregnant woman (started as early as 4 wk of gestation) and continued during delivery (2 mg/kg loading dose IV followed by 1 mg/kg/hr IV) and in the newborn for the 1st 6 wk of life (2 mg/kg every 6 hr PO). In the developed world, such therapy has been documented to decrease the rate of perinatal HIV-1 transmission to <8%.>1,000 copies/mL should be counseled about the potential benefit of cesarean section in reducing the risk for vertical transmission.

Retrospective data suggest that even if a mother has received no anti-retroviral therapy during gestation or delivery, the 6-wk component of the ZDV prophylactic regimen instituted for the newborn as soon as possible after delivery (preferably within 12–24 hr of birth) results in a significant reduction of transmission rate. Full-term infants should be given oral ZDV at a dose of 2 mg/kg every 6 hr for 6 wk. Reduced dosages are used for preterm infants (see Table 5 ).

A study evaluating the efficacy of oral nevirapine, a non-nucleoside reverse transcriptase inhibitor, given once to women in labor and once to the infant during the 1st 48–72 hr of life, capitalizes on the prolonged half-life of this drug. In Africa it has been shown to reduce perinatal transmission by 50%, providing a simple and highly cost-effective regimen for resource-poor countries. For women living in resource-constrained settings, the WHO has recommended that pregnant women be treated with an anti-retroviral regimen appropriate for their own health if possible. For those who do not meet indications for or have no access to therapy, a regimen known to prevent vertical HIV-1 transmission should be offered, such as ZDV from 28 wk of pregnancy plus a single dose of nevirapine (SD NVP) during labor and 1 wk of ZDV therapy for the neonate. International studies are under way to determine optimal approaches to interruption of perinatal transmission in breast-fed infants. Studies in non-breast-feeding pregnant women in Thailand have shown that 3rd trimester ZDV with SD NVP in labor with 7 days of ZDV ± SD NVP to the infant was associated with a transmission rate of 3%.