Management of HIV-AIDS in children

Pre ART care

Care of the HIV infected child starts with pre-ART care. Pre-ART care includes:

• Assessment of  growth and nutritional status
• Assessment of immunization status and provide appropriate immunization.
• Ensure that the child is on cotrimoxazole prophylaxis
• Assessment for signs and symptoms of opportunistic infections including TB.
• Assigning stage of disease using WHO clinical staging and immunological criteria and assess whether the child fits the criteria for starting ART

Good pre-ART care of the infected child with support to the family as comprehensive care for the family unit is important as this sets the stage for future care and better response to treatment

Nutrition in CLHA:

Malnutrition is a common condition in CLHA and is major contributor to mortality in them. Weight loss has resulted in increased infectious complications in children and wasting (i.e. low weight for height/ length) has been associated with reduced survival. Malnutrition in CLHA occurs because of variety of reasons. Nutritional requirements are increased in CLHA even in absence of acute infections. Acute infections lead to further increase in nutritional requirement. The child has reduced appetite due to infections and anemia. Conditions like oral thrush and similar lesions of oral cavity and esophageal candidiasis may lead to inability to take food or dysphagia. CLHA may have nausea and vomiting as result of infections and side effects of drugs.  Persistent diarrhea, which is quite common among CLHA may be associated with malabsorption. In addition, CLHA suffer from psychological problems which may lead to failure to thrive.

The patients should be provided adequate nutrition in terms of protein and calories taking into account their nutritional status. It is recommended to increase the energy intake of HIV-infected infants and children by 10% of the RDA for their age and sex if they are asymptomatic, and by 20−30% of the RDA if they are symptomatic or recovering from acute infections. The need for micronutrient supplementation should be assessed and CLHA should be provided the deficient micronutrients. Supplementation with vit A should be ensured. Oral and esophageal conditions interfering with feeding and diarrheal illnesses should be promptly treated. Infections and OIs also need to be treated promptly.

Mothers should be counseled for breastfeeding. The counseling should also include regarding use of energy dense food, use of locally available good foods.

Monitoring growth and nutritional status:

As a consequence of above factors CLHA have growth retardation, stunting and severe acute malnutrition. Growth (measurement of weight, length or height, and head circumference) is a sensitive indicator of optimal nutrition and of HIV disease progression and response to ART. Nutritional assessment should include assessment of current nutritional status, diet and nutrition-related symptoms. In the infants nutritional assessment should be done every month. Thereafter, children should be weighed at each visit and full nutritional assessment should be made every three months unless the child in question requires particular attention because of growth problems.

Immunization in CLHA:

Immunization is an effective strategy to prevent infections. In CLHA, the issue regarding immunization revolves around ability of vaccines to mount response as they are immunodeficient and for the same reason the fear of development of disease when live vaccines are used. However, most children are asymptomatic and not severely immunodeficient at the age when vaccines under national immunization programme are administered. BCG, OPV, DPT, Hepatitis B, Measles and MMR can be administered at routine age if the child is asymptomatic or has only mild symptoms. Live vaccines should not be given to children who are symptomatic and severely immunodeficient.  Inactivated polio vaccine is now available in the country and can be considered in place of OPV. Hepatitis B vaccine is recommended using double dose as most immunodeficient children will have inadequate response to usual dose. Hemophilus influenza vaccine is not in national immunization schedule but must be considered in HIV infected children.

It is important to remember that all HIV infected children should be assessed for their clinical status at each visit before giving live vaccines.

Screening for OIs and treatment and Cotrimoxazole prophylaxis:

Cotrimoxazole prophylaxis (CPT) prevents Pneumocystis jiroveci pneumonia (PCP - formerly Pneumocystis carinii pneumonia), toxoplasmosis and other bacterial infections. CPT  is a simple, well-tolerated and cost-effective intervention for CLHA and is now considered standard of care.

Indications for CPT:

• All HIV exposed infants from 6 weeks of age until HIV infection is excluded.
• All HIV infected infants
• All HIV infected children between 1-5 years WHO stage (see later) 2,3 and 4 or CD 4 < 25 %
• All symptomatic HIV infected children above 5 years:
• WHO stage 2, 3 and 4 if CD4 counts not available, or
• WHOn stage 3 or 4 irrespective of CD4 count, or
• CD 4 count < 350/mm3 irrespective of WHO staging
• As secondary prophylaxis (after initial PCP treatment):
• < 5 years- do not stop
• > 5 years- consider stopping if counts > 350/ mm3 on two occasions at least 3 months apart

Following table shows the dose of co-trimoxazole (CTX) tablet/ syrup. Recommended dose is 5 mg/kg/day orally.

CTX dose for PCP prophylaxis

Weight (Kg)	Approx Age	CTX once daily
		Syp 5 ml (40 TMP, 200 SMX)	Child tab (20 TMP, 100 SMX)	Single strength adult tab (80 TMP, 400 SMX)	Double strength adult tab (160 TMP, 800 SMX)
< 5	6wk-2 mo	2.5 ml	1	-	-
5-10	2-12mo	5 ml	2	½	-
10-15	1-2 yr	7.5 ml	3	½	-
15-22	2-5 yr	10 ml	4	1	½
>22	>5 yr	15 ml	-	1 ½	½ -1 depending on weight

CPT can be discontinued in HIV exposed infants when HIV infection is excluded and mother is no longer breast-feeding the child. In HIV infected children, CPT once started should continue till 5 years age. Beyond 5 years, CPT can be stopped after immune restoration evidenced by CD 4 count > 350 cells/mm3 on two occasions not less than 3 months apart. Care givers should understand that cotrimoxazole does not treat and cure HIV infection. Counsel caregivers well for side-effects to CTX although these are not common. If the adverse reactions to CTX necessitate its withdrawal, the alternative drug is dapsone (2 mg/kg once daily) if available.

ART

ART forms the backbone of treatment of CLHA. ART once started has to be taken lifelong. It also has to be taken strictly as per schedule. Besides, it requires regular monitoring. All these factors demand careful patient selection. The decision to start ART is based on the clinical and immunological status of CLHA. WHO clinical staging is used for standardization of defining clinical severity of the given patient. Detailed clinical history and physical examination are necessary for assigning WHO clinical stage.

Before starting ART, the patients’ infections or OIs should be treated adequately. The primary caregiver should be identified. The patient or caregiver should undergo 2-3 sessions of ART counseling.  

Clinical criteria to initiate ART in CLHA:

Clinical staging in HIV-infected children not yet taking ART predicts disease progression and mortality. Clinical staging can be used to guide when to start cotrimoxazole and when to start ART even in situations where CD4 count is not available. WHO clinical staging categorizes HIV infected children in following 4 categories:

WHO stage 1: Asymptomatic

WHO stage 2: Mild                                                                              

WHO stage 3: Advanced

WHO stage 4: Severe

Details of clinical signs and diseases used for WHO clinical staging are in the table II.

WHO Clinical staging for infants and children for confirmed HIV Infection:

Clinical Stage 1

Asymptomatic, or only

Persistent generalized lymphadenopathy

Clinical Stage 2

Unexplained persistent hepatosplenomegaly

Papular pruritic eruptions

Extensive wart virus infection

Extensive molluscum contagiosum

Recurrent oral ulcerations

Unexplained persistent parotid enlargement

Lineal gingival erythema

Herpes zoster

Recurrent or chronic upper respiratory tract infections (otitis media, otorrhoea, sinusitis, tonsillitis)

Fungal nail infections

Clinical Stage 3

Unexplained moderate malnutrition not adequately responding to standard therapy

Unexplained persistent diarrhoea (14 days or more )

Unexplained persistent fever (above 37.5oC intermittent or constant, for longer than one month)

Persistent oral candidiasis (after first 6-8 weeks of life)

Oral hairy leukoplakia

Acute necrotizing ulcerative gingivitis/periodontitis

Lymph node TB

Pulmonary TB

Severe recurrent bacterial pneumonia

Symptomatic lymphoid interstitial pneumonitis

Chronic HIV-associated lung disease including bronchiectasis

Unexplained anaemia (<8g/dl ), neutropenia (<0.5X 109/L3) or chronic thrombocytopenia (<50 x 109/L3)

Clinical Stage 4

Unexplained severe wasting, stunting or severe malnutrition not responding to standard therapy

Pneumocystis pneumonia

Recurrent severe bacterial infections (e.g. empyema, pyomyositis, bone or joint infection, meningitis, but excluding pneumonia)

Chronic herpes simplex infection; (orolabial or cutaneous of more than one month’s duration or visceral at any site)

Extrapulmonary TB

Kaposi sarcoma

Oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs)

Central nervous system toxoplasmosis (after one month of life)

HIV encephalopathy

Cytomegalovirus infection: retinitis or CMV infection affecting another organ, with onset at age over 1 month.

Extrapulmonary cryptococcosis (including meningitis)

Disseminated endemic mycosis (extrapulmonary histoplasmosis, coccidiomycosis)

Chronic cryptosporidiosis

Chronic isosporiasis

Disseminated non-tuberculous mycobacteria infection

Cerebral or B cell non-Hodgkin lymphoma

Progressive multifocal leukoencephalopathy

Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy

Immunological criteria to initiate ART in CLHA:

CD4 count is used to assess the immunological status of the HIV-infected child. CD4 counts are higher in infants compared to that of adults, and fall to adult values by age 5 years. CD4 % varies less than CD4 counts, hence considered more valuable in children < 5 years of age.

Percentage of CD4 cells can be calculated using the following formula when only the CD4 absolute count is available:

% CD4 count = (Absolute CD4 lymphocyte count / Total lymphocyte count) x 100.

Absolute CD4 +T-lymphocyte count: as obtained by the flowcytometer.

Total lymphocyte count can be obtained by a cell counter or alternatively obtained using TLC and percentage of lymphocytes in DLC.

Following table describes revised classification of immune status based on CD 4 counts:

Revised classification of immune status based on CD 4 counts in children:

Classification of HIV associated immunodeficiency	Age-related CD4 cell values
	< 11 months            (%)	12 - 35 months           (%)	36-59 months          (%)	≥ 5 years      (cells/mm3)
Not significant (normal CD 4 cells)	> 35	> 30	> 25	> 500
Mild	30 – 35	25 – 30	20 – 25	350−499
Advanced	25 – 30	20−25	15−20	200−349
Severe	<25 % or < 1500 cells/mm3	<20 or <750 cells/mm3	<15 or <350 cells/mm3	<15% or <200 cells/mm3

ART Initiation: ART initiation takes into account both- clinical and immunological status of the child. Following table outlines the indications for starting ART in CLHA based on clinical and immunological staging:

Clinical and Immunological criteria to initiate ARTl

al WHO  Clinical Stage	Availability of CD4 cell measurements	Age-specific treatment recommendation
		<12 months*	≥12 months
IV	CD4	Treat all
	No CD4
III	CD4		Treat all, CD4 guided in those children with TB, LIP, OHL, thrombocytopenia
	No CD4		Treat all
II	CD4	CD4 guided
	No CD4	Don’t Treat
I	CD4	CD4 guided
	No CD4	Don’t Treat

*According to current NACO guidelines all infants under 12 months age should be started on ART irrespective of their clinical and immunological status (in the absence of DNA PCR, presumptive diagnosis of severe HIV disease in infants can be made if the infant is antibody positive or mother HIV positive and diagnosis of AIDS indicator disease such PCP pneumonia is confirmed or such an infant has two of the following conditions-oral thrush, severe pneumonia and severe sepsis).

In children over 5 year age, adult cut-off for CD4 counts is used. According to current NACO guidelines, CD4 cut-off to be used is 350/ mm3 and not 200/ mm3 as used for defining severe immunodeficiency.

ART preparedness

Before enrollment in ART, it is necessary to have 2 to 3 counseling sessions to confirm their preparedness for ART to ensure long-term adherence to the therapy. Preparedness for ART involves willingness to adhere to ART. The counseling should focus on assessment of the child, the caregiver and the family. Mother, father or the caregiver should be identified. The caregiver, family and the child should understand the nature of the disease, importance of ART adherence and expected outcome with treatment. Caregiver should clearly understand what drugs, in what doses and at what time of the day are to be given. Child should be assessed for his nutritional, developmental, emotional and health status. Whether the child is receiving CPT or other prophylaxis or any other treatment should be taken note of. Any financial issues and issues related to travel to ART centre should be sorted out.

Paediatric ART regimen, dose and formulations:

Paediatric formulations in the form of fixed dosed combinations (FDC)are provided at all ART centers. FDC tablets supplied under the national initiative will cover > 5 kg children (based on weights). For children < 5 kg body weight, ARVs have to be in form of syrups or suspension. It is recommended NOT to cut adult drugs.

Effective therapy needs at least 3 drugs from different ARV drug class together.

The current NACO pediatric first-line regimen is 2NRTI + 1NNRTI.

The regimens for use in children have been labeled as P I , PIa , P II , PII a, PIII, PIIIa, PIIIb, PIV and PIV a  

Current First Line ART regimen for Children

National Paediatric ART Regimen	Type of Regimen	Regimen	Remarks
Regimen P I	First-line regimen	Zidovudine+Lamivudine + Nevirapine	Preferred paediatric regimen for starting ART
Regimen P I (a)		Stavudine + Lamivudine + Nevirapine	This regimen is for  children starting ART who have  Hb ≤9 g/dL
Regimen P II		Zidovudine+Lamivudine + Efavirenz	Preferred for children on anti-tuberculosis treatment; Hb >9 g/dL and age > 3 yr and weight > 10 kg
Regimen P II (a)		Stavudine + Lamivudine + Efavirenz	For children on anti-tuberculosis treatment; Hb ≤9  g/dL and age > 3 yr and weight > 10 kg
Regimen P III	Alternative first-line regimen	Abacavir + Lamivudine + Nevirapine	For patients not tolerating AZT or d4T on a NVP-based regimen
Regimen P  III (a)		Abacavir + Lamivudine + Efavirenz	For patients not tolerating AZT or d4T on a EFV-based regimen
Regimen P  III (b)		Abacavir + Lamivudine + Lopinavir/Ritonavir	For patients not tolerating AZT or d4T on a LPV/r-based regimen eg. infants started on LPV/r due to prior exposure to PPTCT regimens containing NNRTI(NVP or EFV).
Regimen P IV		Zidovudine + Lamivudine + Lopinavir/Ritonavir	For patients not tolerating both NVP and EFV, and Hb >9 g/dL
Regimen P IV (a)		Stavudine + Lamivudine + Lopinavir/Ritonavir	For patients not tolerating both NVP and EFV and Hb ≤9 g/dL

Current NACO recommendations for pediatric ART use are as follows:

• Zidavudine based regimen (P-I) is the preferred regimen for new ART initiation. As anemia is a common side effect of Zidavudine, this regimen is recommended for children who have Hb more than 9 gm/dl .
• P-Ia, the regimen containing Stavudine in place of Zidavudine is recommended for children having Hb 9 gm/dl or less .
• Niverapine is not used when the patient needs to be given ART and rifampicin based ATT. Such cases need to be given Efavirenz  containing regimen P-II if the patient does not have anemia. In anemic patients needing ATT and ART, stavudine, lamivudine and efavirenz (regimen P-IIa) is indicated.  Rifampicin lowers NVP drug level by 20-58% and EFV drug level by 25%. After 2 weeks of completing rifampicin-based anti-TB treatment, switch back to standard first line regimen with 2NRTI + NVP.
• Alternative first line regimen P-III (Abacavir + Lamivudine + Nevirapine) is for patients not tolerating Zidavudine and Stavudine both on a NVP-based regimen.
• Regimen P-IIIa (Abacavir + Lamivudine + Efavirenz) is indicated for patients not tolerating Zidavudine and Stavudine both on Efavirenz based regimen.
• Regimen P-IIIb (Abacavir + Lamivudine + Lopinavir/Ritonavir) is indicated for patients not tolerating Zidavudine and Stavudine both on a ritonavir boosted lopinavir (LPV/r)-based regimen eg. infants started on LPV/r due to prior exposure to NVP or EFV in PPTCT regimen.
• Regimen P-IV (Zidovudine + Lamivudine + Lopinavir/Ritonavir) is indicated in children who do not tolerate NVP and EFV and have Hb >9 g/dL.
• Regimen P-IVa (Stavudine + Lamivudine + Lopinavir/Ritonavir) is indicated in children who do not tolerate NVP and EFV and have Hb <9 g/dL.

The ARVs are available as fixed dose combinations (two or three drugs FDC). For accurate dosing and ease of remembering the doses have been “harmonized”for weight bands. Looking at the harmonized dosing chart (see below), it can be seen that children for a particular weight need to be given same number of tablets irrespective of regimen they need.

Harmonized Dosing chart for pediatric regimens:

	Drug	Child Strength (mg)	3-5.9 kg	6-9.9 kg	10-11.9 kg	12-13.9 kg	14-14.9 kg	15- 16.9 kg	17-19.9 kg	20-24.9 kg	Adult Strength (mg)	25-29.9 kg	30-34.9 kg
First line Regimens. Dosing is tabs twice daily	AZT/3TC/NVP	60/30/50	1	1.5	2	2	2.5	2.5	2.5	3	300/150/200	1	1
	AZT/3TC	60/30	1	1.5	2	2	2.5	2.5	2.5	3	300/150	1	1
	d4T/3TC/NVP	6/30/50	1	1.5	2	2	2.5	2.5	2.5	3	30/150/200	1	1
	d4T/3TC	6/30	1	1.5	2	2	2.5	2.5	2.5	3	30/150	1	1
First line substitution, dosing is tabs or syrup twice daily	ABC/3TC	60/30	1	1.5	2	2	2.5	2.5	2.5	3	Single formulation ABC 300 and 3TC 150	1	1
	NVP	50mg/5ml	5 ml	8 ml	10 ml	10 ml	15 ml	15 ml	15 ml	15 ml	200 mg	1	1
	EFV OD	200	x	x	1	1	1	1	1	1.5		1.5	2
	EFV OD	50	x	x	x	X	x	1	1	X		1	X

ART in HIV and TB co-infection

TB should be suspected among children presenting with fever and / or cough for more than 2 weeks, with or without weight loss or no weight gain; and history of contact with a suspected or diagnosed case of active TB disease within the last 2 years. Diagnosis should be based on a combination of clinical presentation, sputum examination wherever possible, Chest X ray (PA view), Mantoux test (1 TU PPD RT23 with Tween 80, positive if induration >10mm after 48‐72 hours) and history of contact. Diagnosis should be made by a Medical Officer and the existing RNTCP case definitions be used for all cases diagnosed. Children showing neurological symptoms like irritability, refusal to feed, headache, vomiting or altered sensorium may be suspected to have TB meningitis. Where diagnostic difficulties are faced, the child should be referred to a pediatrician for further management.

All pediatric TB cases diagnosed should be registered under the RNTCP and intermittent short course chemotherapy (SCC) be given under direct observation as per the RNTCP policy. All newly diagnosed TB infection in CLHA need to be treated on category I ATT.

Use of ART among patients with TB can lead to sustained reductions in HIV viral load, immune restoration, decrease in AIDS defining illness, and decreased mortality. This benefit is seen across all CD4 cell counts. Taking antiretroviral drug at the same time as TB treatment has been shown to reduce the death rate by 50 % when compared with delaying ART until after TB treatment was completed.

ART should be initiated within 2 weeks of starting ATT in cases having extra-pulmonary TB and those with pulmonary TB having CD4 count <350/mm3. In those children with pulmonary TB and HIV with higher CD4 counts, ART initiation can be delayed taking into account the pill burden, acceptance and tolerance of ATT.

Side effects and toxicity of ARVs:

Children receiving ART should be monitored for occurrence of side/ adverse effects. With mild adverse effects

(AE), the drug may still be tolerated. Occasionally the AE may be severe and necessitate drug cessation or discontinuation of the drug. In addition to ARVs, the patients frequently need co-trimoxazole, anti-tubercular drugs and various other drugs. The symptoms related to AE may sometime be same that occur due to OIs. Therefore, its important to carefully analyse the situation before occurrence of a particular symptom is ascribed to drug AE. For example, occurrence of jaundice in child receiving ART and ATT may be on account of toxicity of rifampicin, ARVs or due to an OI-viral hepatitis.

Common side effects of commonly used ARVs in pediatric formulations are summarized below:

Zidovudine (ZDV, AZT):

Haematological AEs are common with zidovudine. Anemia and neutropenia occurs in 20-40% of symptomatic children. The cutoff-point for Hb in national ART guidelines for initiating ART with AZT based regimen is 9.0 g/dL. Close follow-up for Hb (Hb tests to be done for at 15 days, 1 month, 2 months, 3 months and six months) is recommended. Increased bone marrow suppression noted with following drugs:cotrimoxazole, dapsone and ganciclovir.

Other AEs with AZT include headache, hepatotoxicity and myopathy. Should not be administered with stavudine because the two drugs antagonize each other leading to decreased efficacy.

Stavudine (d4T):

Gastrointestinal disturbances and headache are usually mild. Other AEs include mitochondrial toxicity leading to lactic acidosis, peripheral neuropathy (irreversible), lipodystrophy and pancreatitis. Mitochondrial toxicities are more likely when co-administered with ddI (also with INH, phenytoin).

Lamivudine (3TC):

Lamivudine is known for its minimal toxicity. Headache, nausea, diarrhea, skin rash and abdominal pain are mild side effects. Pancreatitis and lactic acidosis have occasionally been treported.

Nevirapine (NVP):

Skin rash is the most common adverse event recorded with NVP which can be mild  to severe/ life-threatening (ie. Steven-Johnson’s). Hepatotoxicity is also known AE which is increased in patients starting with high CD4 counts. Hepatotoxicity can be minimized by using half dose to start with (the lead-in period). However, if the child is already on an EFV-based regimen, and should be put back on NVP, a lead-in dose of NVP is not required. NVP is a potent inducer of Cytochrome P450 CYP3A4. Rifampicin decreases the NVP concentration by 37%. For this reason and because of occurrence of hepatotoxicity with both drugs, rifampicin and NVP are not used together.

Efavirenz (EFV):

Skin rash similar to NVP is known to occur with EFV.  Other side effect include central Nervous system effects including somnolence, insomnia, abnormal dreams, confusion, abnormal thinking, hallucinations, impaired concentration and euphoria. Hepatitis is also described.. EFV has been found to be teratogenic in primates (neural tube defects), therefore it should not be given to pregnant women.

Because of CNS effects, EFV is not recommended for use with antihistamines or sedatives. Rifampicin, phenobarbital, phenytoin decrease levels of EFV and co-administration may require adjusting the dose. Efavirenz decreases the concentration of clarithromycin but not of azithromycin.

Abacavir (ABC):

Common side effects of ABC include nausea and vomiting, diarrhea, rash, malaise and headache

Hypersensitivity Reaction occur in  less than 5% of adults and children. It occurs  usually during first 6 weeks of therapy, but may occur at any time and includes fever, fatigue, diarrhea, vomiting, abdominal pain, arthralgias, respiratory symptoms, increased liver enzymes, lymphadenopathy, mucus membrane ulcerations, rash. It is potentially fatal. In such situations, immediate stoppage of drug is required. ABC should never be restarted in such cases.

Lopinavir boosted by ritonavir (LPV/r)

Side Effects of LPV/r include diarrhea, headache, nausea and vomiting, rash, fat redistribution and lipid abnormalities, pancreatitis, hepatitis, hyperglycemia and frank diabetes mellitus.

The AE/ drug toxicity should be carefully evaluated and graded for severity. Following is grading of ARV toxicity and suggested action:

• Grade 1 Mild reactions: symptoms are mild and transient, do not require medical intervention/ therapy.
• Grade 2 Moderate reactions: mild to moderate limitation of activity, some assistance needed, no or minimal medical intervention/ therapy required.  Some moderate reactions (e.g. lipodystrophy or peripheral neuropathy) do require substitution. For other reactions consider continuation of ART as long as feasible; if patient does not improve on symptomatic therapy, consider single drug substitution.

• Grade 3 Severe reactions; limitation of activity, some assistance required usually, medical intervention/ therapy required with possible hospitalization. May need substitute the offending drug without discontinuing ART
• Grade 4 Severe life-threatening reactions: Extreme limitation of activity, significant assistance required, significant medical intervention/ therapy needed; hospitalization or hospice care needed.  Immediate discontinuation of all ARV drugs is recommended. Manage the medical event (i.e. symptomatic and supportive therapy) and re-introduce ARVs using a modified regimen (i.e. with an ARV drug substitution for the offending drug) when patient is stabilized.

Following table gives criteria for grading of severity of common drug toxicity:

General guidance to estimating severity grade

Parameter	Grade 1 (Mild)	Grade 2 (Moderate)	Grade 3 (Severe)	Grade 4 (Severe life-threatening)
Characterization of symptoms and general guidance on management	Symptoms causing no or minimal interference with usual social and functional activities No therapy needed, monitor	Symptoms causing greater than minimal interference with usual social and functional activities May require minimal intervention and monitoring	Symptoms causing inability to perform usual social and functional activities Requires medical care and possible hospitalization	Symptoms causing inability to perform basic self-care functions Requires medical or operative intervention to prevent permanent impairment, persistent disability, or death

HAEMATOLOGY

Absolute neutrophil count	750 – <1,000/mm3	500 – 749/mm3	250 – 500/mm3	<250/mm3
Haemoglobin (child >60 days of age)	8.5 – 10.0 g/dL	7.5 - <8.5 g/dL	6.5 – <7.5 g/dL	< 6.5 g/dL Or severe clinical symptoms due to anaemia (e.g., cardiac failure) refractory to supportive therapy
Platelets	100,000-<125,000/mm3	50,000-<100,000/mm3	25,000-<50,000/mm3	<25,000/mm3 Or bleeding

GASTROINTESTINAL/ HEPATIC

Clinical
Diarrhoea ≥ 1 year of age < 1 year of age	Transient or intermittent episodes of unformed stools OR increase of ≤ 3 stools over baseline per day Liquid stools (more unformed than usual) but usual number of stools	Persistent episodes of unformed to watery stools OR increase of 4 – 6 stools over baseline per day Liquid stools with increased number of stools OR mild dehydration	Grossly bloody diarrhoea OR increase of ≥ 7 stools per day OR IV fluid replacement indicated Liquid stools with moderate dehydration	Life-threatening consequences (e.g., hypotensive shock) Liquid stools resulting in severe dehydration with aggressive rehydration indicated OR hypotensive shock
Nausea	Transient (< 24 hours) or intermittent nausea with no or minimal interference with oral intake	Persistent nausea resulting in decreased oral intake for 24 – 48 hours	Persistent nausea resulting in minimal oral intake for > 48 hours OR aggressive rehydration indicated (e.g., IV fluids)	Persistent nausea with no or minimal oral intake resulting in dehydration with aggressive rehydration indicated
Pancreatitis	NA	Symptomatic AND hospitalization not indicated (other than emergency treatment)	Symptomatic AND hospitalization not indicated (other than emergency treatment)	Life-threatening consequences (e.g., circulatory failure, haemorrhage, sepsis
Vomiting	Transient or intermittent vomiting with no or minimal interference with oral intake	Frequent episodes of vomiting with no or mild dehydration	Persistent vomiting resulting in orthostatic hypotension OR Aggressive rehydration indicated (e.g., IV fluids)	Life-threatening consequences (e.g., hypotensive shock)

GASTROINTESTINAL/ HEPATIC

Laboratory
ALT (SGPT)	1.25 – 2.5 x ULN	2.6 – 5.0 x ULN	5.1 – 10.0 x ULN	> 10.0 x ULN
AST (SGOT)	1.25 – 2.5 x ULN	2.6 – 5.0 x ULN	5.1 – 10.0 x ULN	> 10.0 x ULN
Bilirubin (>2 weeks of age)	1.1 – 1.5 x ULN	1.6 – 2.5 x ULN	2.6 – 5.0 x ULN	> 5.0 x ULN
Lipase	1.1 – 1.5 x ULN	1.6 – 3.0 x ULN	3.1 – 5. 0 x ULN	> 5.0 x ULN
Pancreatic Amylase	1.1 – 1.5 x ULN	1.6 – 2.0 x ULN	2.1 – 5.0 x ULN	> 5.0 x ULN

ALLERGIC/DERMATOLOGIC

Acute systemic allergic reaction	Localized urticaria (wheals) lasting a few hours	Localized urticaria with medical intervention indicated OR mild angioedema	Generalized urticaria OR angiooedema with medical intervention indicated OR symptomatic mild bronchospasm	Acute anaphylaxis OR life-threatening bronchospasm or laryngeal oedema
Cutaneous reaction – rash	Localized macular rash	Diffuse macular, maculopapular, or morbilliform rash OR target lesions	Diffuse macular, maculo-papular, or morbilliform rash with vesicles or limited number of bullae OR superficial ulcerations of mucous membrane limited to one site	Extensive or generalized bullous lesions OR Stevens- Johnson syndrome OR ulceration of mucous membrane involving two or more distinct mucosal sites OR Toxic Epidermal Necrolysis (TEN)

NEUROLOGIC

Alteration in Personality – behaviour or in mood	Alteration causing no or minimal interference with usual social and functional activities	Alteration causing greater than minimal interference with usual social and functional activities	Alteration causing inability to perform usual social and functional activities AND intervention indicated	Behaviour potentially harmful to self or others OR life-threatening Consequences
Altered Mental Status	Changes causing no or minimal interference with usual social and functional activities	Mild lethargy or somnolence causing greater than minimal interference with usual social and functional activities	Onset of confusion, memory impairment, lethargy, or somnolence causing inability to perform usual social and functional activities	Onset of delirium, obtundation, or coma
Neuromuscular weakness (including myopathy and neuropathy)	Asymptomatic with decreased strength on exam OR minimal muscle weakness causing no or minimal interference with usual social and functional activities b	Muscle weakness causing greater than minimal interference with usual social and functional activities b	Muscle weakness causing inability to perform usual social and functional activities b	Disabling muscle weakness causing inability to perform basic self-care functions OR respiratory muscle weakness impairing ventilation
Neurosensory alteration (including painful neuropathy)	Asymptomatic with sensory alteration on exam OR minimal paraesthesia causing no or minimal interference with usual social and functional activities	Sensory alteration or paraesthesia causing greater than minimal interference with usual social and functional activities	Sensory alteration or paraesthesia causing inability to perform usual social and functional activities	Disabling sensory alteration or paraesthesia causing inability to perform basic self-care functions c