Opportunistic Infections

in
Children Living with HIV
Part 1: Bacterial & Fungal OIs
 Session Objectives
By the end of the session, the participants will be able to:
• Learn what are the common Opportunistic Infections (OIs) in Children Living with HIV
(CLHIV)
• Assess and classify an infant/child for severe infection as per the Integrated
Management of Neonatal and Childhood Illnesses (IMNCI) strategy
• Learn the differential diagnosis of Pneumonias

• Understand the clinical features and management of:

o Common bacterial infections (pneumonias, meningitis, sepsis, abscesses etc.)

o Common fungal infections (Candidiasis, Cryptococcal meningitis and Talaromycosis)

Common OIs in Infants/Children Living with HIV
Bacterial infections: Fungal infections:
Streptococci Candida
Staphylococci
Pneumocystis
Pneumococci
H. Influenza type b Cryptococcus
Mycobacteria Talaromycosis

Viral infections : Protozoal infections:

Cytomegalovirus
Toxoplasma
Herpes Simplex Virus
Varicella Cryptosporidium
Herpes zoster Isospora
 Common Bacterial OIs in CLHIV
Bacterial infections are common, recurrent and serious in children
A child who is HIV infected is equally prone to develop bacterial infections as a
child who is not HIV infected
• Recurrent Bacterial Infections are the commonest OIs in CLHIV
• Pneumonias are the most commonly occurring bacterial infection.
• Others infections are:
• Sepsis
• Abscesses
• Otitis media
• Osteomyelitis and Septic arthritis
• Meningitis
 Common Bacterial OIs and their Causative organisms
Infections Pneumonias Meningitis Osteomyelitis Sepsis Abscesses

Causative • S. pneumoniae • H. Influenzae b • Staph aureus • Gram negative • Staph. aureus

organisms • H. influenzae b • S. pneumoniae • Klebsiella bacteria • S. pyogenes
• Staph. aureus • Proteus • Staph aureus
• Staph. aureus • Pseudomonas • Anaerobes
• Klebsiella • Salmonella • Enterobacter
• Proteus
• Pseudomonas
• E. Coli
• Mycoplasma

Management of Bacterial Infections:

• Empiric antibiotics initially
• Change to appropriate antibiotics based on culture and sensitivity, when available
Integrated Management of Neonatal and Childhood Illnesses (IMNCI)

Goals of IMNCI:
• Standardized case management of sick new‐born and children
• Focused on most common causes of mortality in infants and children
• Improve illness recognition and timely referral
Tools for Assessment: Ask, Look, Listen, and Feel
Two Age-groups:
(A)Young infants: From birth up to 2 months of age
(B) Older infants/children: From 2 months up to 5 years
Case Management Process as per IMNCI
Assess the Child

Classify the Illness

Identify Treatment

Urgent referral required Urgent Referral Not Required

Give Pre-referral Treatment Treat the Child

Refer the Child Counsel the mother & ensure Follow up

 Step-1: Assessment of child- IMNCI
Check for General Danger Signs: If present refer for Admission

Source: IMNCI Physician Chart booklet 2016

 Step-2: Assess the child & Classify the illness
• Assess the child for:
• Cough or difficult breathing
• diarrhea
• fever
• Check for:
• Immunization status
• Nutritional status: signs of malnutrition, anaemia, vitamin deficiency
• any other problem which might not have been addressed till now
• Classify the illness: means making a decision on the basis of severity of the illness
based on the signs present
• Preferably refer a sick child to a Pediatrician for evaluation and management
 Does the child have cough or difficult breathing?
SIGNS CLASSIFY IDENTIFY TREATMENT
Any danger sign or SEVERE PNEUMONIA OR • Give first dose of an appropriate antibiotic
stridor in calm child? VERY SEVERE DISEASE • Refer URGENTLY to hospital
Chest in drawing or PNEUMONIA • Give oral amoxicillin for 5 days
fast breathing? • If wheezing (or disappeared after inhaled bronchodilator) give
inhaled bronchodilator for 5 days
• If chest in drawing in HIV exposed/infected, give first dose of
amoxicillin and refer
• Soothe the throat and relieve cough with a safe remedy
• If recurrent cough/cough>14 days, refer for possible
asthma/TB assessment
• Advise mother when to return immediately
• Follow up in 3 days

No signs of COUGH OR COLD • Soothe the throat and relieve cough with a safe remedy
pneumonia or very • If recurrent cough/cough>14 days, refer for possible
severe disease asthma/TB assessment
• Advise mother when to return immediately
• Follow up in 3 days

Source: Adapted from IMNCI Physician Chart booklet, 2016

 Does the child have diarrhoea?
IF YES, ASK:
• Duration of diarrhoea?

• Any blood in stools?

LOOK AND FEEL THE CHILD AND FIND OUT:

• General condition: lethargic or unconscious /restless or irritable

• Look for sunken eyes

• Offer the child fluid: not able to drink or drinks poorly/drinks eagerly or thirsty

• Pinch the skin of the abdomen: does it go back very slowly taking >2sec/slowly?
 How to Assess and Classify dehydration?
SIGNS CLASSIFY IDENTIFY TREATMENT
2 of the following signs: severe SEVERE • REFER URGENTLY to hospital with mother giving
dehydration DEHYDRATION frequent sips of ORS on the way. Advise to continue
• Lethargic or unconscious breast feeding
• Sunken eyes • if child >2 years and there is cholera in that area, give
• Not able to drink/drink poorly antibiotic for cholera
• Skin pinch goes back very slowly

2 of the following signs: some
dehydration
• Restless/irritable
• Sunken eyes
• Drinks eagerly/thirsty
• Skin pinch goes back slowly
SOME • REFER URGENTLY to hospital with mother giving
DEHYDRATION frequent sips of ORS on the way. Advise to continue
breast feeding
• Advise mother when to return immediately
• Follow up in 5 days if not improving

Not enough signs to classify as NO • Give ORS, Zinc supplement and advise home care
some or severe dehydration: DEHYDRATION • Advise mother when to return immediately
• Follow up in 5 days if not improving

Source: Adapted from IMNCI Physician Chart booklet 2016

 How to Classify and Manage Diarrhoea in a child
• Acute diarrhoea: duration <14 days
• Persistent diarrhoea: duration > 14 days
• Dysentery: presence of blood in stools
• Refer to Paediatrician if the child has:
• Persistent diarrhoea: Give ORS, Zinc, single dose of Vitamin A and refer to
paediatrician for evaluation
• Dysentery: Give antibiotic- Cefixime for 3 days, ORS, Zinc and refer to
paediatrician for evaluation
Dose of Zinc:
 Infants less than six months age : 10 mg per day of zinc x 14 days
 age 6 months to 5 years : 20 mg per day of zinc x14 days
 Does the child have fever?
• Fever is a very common symptom and is often the main reason for bringing
children to the doctor
• Causes: minor infections/ sign of a life-threatening illness/ malaria/
meningitis/typhoid fever/ measles / an OI in a CLHIV
• Identify children who need urgent referral with appropriate pre-referral
treatment (antimalarial or antibiotic).
If a child has fever, ask for duration of fever and LOOK FOR:
• Stiff neck
• Runny nose
• Any bacterial cause for fever: local tenderness, oral sores, refusal to use a limb,
hot tender swellings, boils, lower abdominal pain or pain on passing urine
• Look for signs of Measles: generalized rash and one of these: cough ,runny nose,
red eyes
 How to Classify and Treat Fever
SIGNS CLASSIFY IDENTIFY TREATMENT
Any general danger sign or VERY SEVERE FEBRILE • Give first dose of an appropriate antibiotic
stiff neck? DISEASE • Endemic area: Give first dose of artesunate or quinine for
severe malaria
• Treat the child to prevent low blood sugar
• Give one dose of paracetamol for high fever
• Refer URGENTLY to hospital

1. Malaria test POSITIVE, 1.MALARIA • Give recommended oral antimalarial

no danger sign • Give one dose of paracetamol for high fever
• Advise mother when to return immediately
2. Malaria test NEGATIVE, 2.SUSPECTED • Follow up in 2 days if fever persists
no danger sign MALARIA • If fever present everyday for>7 days, REFER

Malaria test NEGATIVE or FEVER NO MALARIA • Give one dose of paracetamol for high fever
other causes of fever • Treat the cause of fever identified
PRESENT(cough/pneumoni • Advise mother when to return immediately
a/ diarrhoea /skin or ear • Follow up in 2 days if fever persists
infection) • If fever present everyday for>7 days, REFER

Source: Adapted from IMNCI Physician Chart booklet, 2016

 Treatment Guidelines as per IMNCI

For detailed treatment

guidelines of a sick child as
per IMNCI for Respiratory
infections, Diarrhoea and
Fever including drug dosages
as per body weight, Refer to
link given below:
:
https://nhm.gov.in/images/p
df/programmes/child-health
/guidelines/imnci_chart_boo
klet.pdf
 Physical examination: Head to Toe
Examination
• General appearance
• Vital signs (HR, RR, BP, temp):
Respiratory distress
Circulatory failure
• Anthropometry
• General physical examination including skin
• Oral, Eye and ENT
• Respiratory
• Abdomen and genito-urinary
• Cardiovascular
• Neurological
• Musculoskeletal
 Pneumonias in CLHIV
• CLHIV have an increased risk of developing pneumonias.
• The usual presenting symptom is cough with or without fast
breathing
• Evaluation and management of pneumonias in CLHIV is similar
to that in HIV uninfected children
• Bacterial Pneumonias usually respond to antibiotics within 3-5
days
• Delayed response beyond 5-7 days would favor a diagnosis of:
• PCP (Pneumocystis jirovecii Pneumonia)
• TB
• Unusual organism e.g. viral or fungal infection Image Courtesy
GHTM / I-TECH Fellowship
• LIP (Lymphoid Interstitial Pneumonitis) Programme, Tambaram,
• Bronchiectasis Chennai
Clinical Evaluation of CLHIV with Symptoms of Pneumonias
Take a detailed history and do Clinical and Laboratory evaluation to
identify the cause of Pneumonia

Pulmonary Causes Non- Pulmonary Causes

• Bacterial Pneumonia • Severe anaemia,

• Wheezy Bronchitis • Sepsis,
• Pulmonary TB • Malaria,
• Pneumocystis Pneumonia (PCP) • Meningitis
• Lymphoid Interstitial Pneumonitis
(LIP)
Pneumocystis Jirovecii (carini)Pneumonia (PCP)
• Most common OI in infants with high mortality rate of 35%
• Incidence is highest during the first year of life
• Usually peaks at 3-6 months of age
• After one year of age, the frequency of occurrence of PCP decreases
• Clinical features in children under one year
• Tetrad of symptoms : (Fever, fast breathing, respiratory distress and cough)
• Clinical Examination: may reveal bilateral basal inspiratory crepitations
with respiratory distress and hypoxia
• In older children:
• PCP may present as an insidious onset of cough and dyspnoea, often with
clubbing
 When to Suspect PCP in Children?
Suspect PCP, if the child is:
• Less than 12 months old
• Has fast breathing (tachypnoea):
• Respiratory Rate >50 /min in age 2 to12
months*
• Has Signs/Symptoms of severe respiratory distress:
• Intercostal and Subcostal retractions  Chest X-Ray findings :
• cyanosis  Earliest: infiltrates are perihilar, progressing
• Has a few pulmonary inspiratory crepitations in peripherally - reaching the apical portions of
lung
relation to the degree of cyanosis  Bilateral diffuse parenchymal infiltrates with
*Respiratory Rate >40/min is considered as “Ground-glass" appearance
tachypnoea in children from age one year to 5 years  Rarely, lobar/cavitary/nodular/ miliary lesions/
pneumothorax/ pneumomediastinum.
 Any HIV infected child with spontaneous
pneumothorax, suspect PCP.
 Investigations to Confirm the PCP
• The provisional diagnosis in a CLHIV can be made on the basis of history,
clinical presentation, chest X-Ray and CD4 count.
• The diagnosis of PCP is confirmed by demonstration of the organism in
pulmonary secretions.
• Specimen Collection:
• Induced sputum after nebulization
• Bronchoscopy with broncho-alveolar lavage
• Fibre-optic bronchoscopy with Transbronchial biopsy
• Stains Used:
• Gomori’s Methenamine, Toluidine Blue, Giemsa or Wright stain
• Demonstration of organism is usually difficult
• The diagnosis may also be confirmed by testing for Monoclonal
immunofluorescent antibodies
 Treatment of Pneumocystis Pneumonia (PCP)
• Oxygen administration
• Cotrimoxazole: 20 mg/kg/day in 4 divided doses for 3 weeks
• Steroids: if hypoxia (pO2 <70 mm Hg)
• Prednisolone: Day 1-5 : dose-2 mg/kg/day PO BD
: Day 6-10 : dose-1 mg/kg/day PO
: Day 11-12 : dose-0.5 mg/kg/day PO
or
• IV Dexamethasone: dose-0.3-0.5 mg/kg 6 hourly for 5 days
• Cotrimoxazole Preventive Therapy
• All CLHIV have to be given cotrimoxazole prophylaxis regardless of Clinical
stage or CD% up to 5 years of age
• CLHIV aged >5 years: Follow adult guidelines
 Lymphoid Interstitial Pneumonitis (LIP)
• Most commonly seen in CLHIV
• WHO clinical stage 3 criterion
• It is a Lympho-proliferative, non-infectious pulmonary disorder
• Characterized by diffuse infiltration of CD4 lymphocytes, plasma cells, and
histiocytes in the alveolar septa and along the lymphatics.
• Clinical features:
• Insidious onset of mild but persistent cough
• with or without exertional dyspnoea and
• breathing difficulty
• The patients also have associated clubbing.
When to suspect Lymphoid Interstitial Pneumonitis (LIP)?
• LIP should be suspected in a child who despite
being given appropriate antibiotics or anti TB
treatment:
• Does not respond to treatment
OR
• The chest X-Ray findings persist
OR
• Chest X-ray findings worsen
• The other differential diagnoses are :
• Pneumocystis Pneumonia (PCP) The x-ray shows diffuse
• Viral and fungal pneumonias interstitial reticular and
• Miliary tuberculosis nodular infiltrates, probably
LIP.
• Lymphomas
How to Differentiate LIP from Miliary TB & PCP?
LIP Miliary TB PCP
Age Older Any Younger
Immuno-
suppression Mild to severe Mild to severe Severe

Chronic cough, Fever, cough, weight Acute onset cough

Clinical features loss + tachypnoea
no fever
Persistent reticulo-
X ray findings nodular opacities +/- Miliary mottling Perihilar diffuse
hilar lymph nodes infiltrates

Response to No response to Responds to Anti-TB Responds to

treatment antibiotics or ATT Treatment (ATT) Cotrimoxazole +
Prednisolone

26
 Diagnosis & Management of LIP

• Diagnosis: Clinical presentation and Exclusion of other similar clinical conditions

• Confirmation by Broncho Alveolar Lavage (BAL)

• Management:

 Nebulized beta agonists and physiotherapy

 Oral prednisolone in chronic hypoxia:

• 1-2 mg/kg/day for 2-4 weeks

• then 0.5 to 1 mg/kg on alternate days for 4-6 weeks, as tolerated

 Mycobacterium avium Complex (MAC)
• MAC infection may due to M avium intracellulare or M paratuberculosis
• MAC can appear as isolated lymphadenitis among HIV infected children
• Defective cell mediated immunity with CD4 count as low as < 50 cells/mm3 is an
important risk factor for development of MAC.
• Common sites involved are lungs, liver, spleen, GI tract, bone marrow and lymph nodes.
• Clinical Features:
Fever with night sweats
Failure to thrive
Fatigue
Chronic diarrhoea and abdominal pain
Lymphadenopathy
Hepato-splenomegaly
Bone marrow involvement (neutropenia, leucopenia, anaemia)
 Diagnosis and Treatment of MAC
Diagnosis:
• Isolation of the organism from blood or biopsy sites (bone marrow, lymph nodes etc.)
• Culture: may be positive in 2 weeks
• Multiple blood cultures are required for species identification
• Anaemia out of proportion to the stage of HIV and raised S. alkaline phosphatase may be
present
Treatment:
• A combination therapy, with a minimum of 2 drugs, is recommended (Clarithromycin or
Azithromycin and Ethambutol or Ciprofloxacin)
• Disseminated disease requires 3 to 4 drugs
• Improvement is seen within 4 to 6 weeks and then treatment to be continued with 2
drugs
 Fungal OIs in Children Living with HIV
• Common Fungal infections in CLHIV are:
• Candidiasis
• Pneumocystis jirovecii pneumonia (PCP)
• Cryptococcosis
• Talaromycosis (previously known as Penicilliosis)
 Oral Candidiasis
• Oral Candidiasis is one of the clinical indicators of HIV infection in infants beyond 8 weeks of
age.
• Candida albicans is the most common among fungal infection in children of which
Oropharyngeal Candidiasis or thrush is the commonest
• Diagnosis: by characteristic curdy white patches which bleed on scraping.
• KOH preparation shows budding yeast cells, hyphae or pseudo hyphae in wet mounts and
culture

Images Courtesy Pediatric CoE, Sion Hospital, Mumbai

 Candidiasis: Clinical Manifestations
1. Oropharyngeal candidiasis (Thrush):
• Recurring / persistent oral thrush in non-breast fed babies beyond 4 weeks of age is a marker of
HIV infection
• There are 3 main morphological presentations:
• Pseudo membranous or hypertrophic
• Erythematous or atrophic
• Angular Cheilitis
2. Oesophageal Candidiasis:
• Is suspected when along with Oral thrush, the child also has:
• refusal to feeds or
• swallowing difficulty especially to solids or
• Drooling of saliva, hoarse voice or
• Stridor or
• Associated odynophagia (retrosternal pain)
3. Vulvovaginal Candidiasis and systemic candidiasis are rare in children
 Candidiasis: Treatment
Oral Candidiasis:
• Nystatin (topical) 1 ml - four times daily – 5 days
• 1% Clotrimazole (topical) - four times daily - 7-14days
• Fluconazole orally 6mg/kg/day for 7-14days
• In resistant cases: Itraconazole 2-5mg/kg/day for 7 days or Amphotericin-B IV
0.3mg/kg/day for 7 days
Oesophageal Candidiasis:
• Fluconazole 6mg/kg/dose once on day 1; maintenance – 3-6 mg/kg/dose once
daily for 4 to 21 days (maximum:400 mg/day)
Systemic Candidiasis:
• Amphotericin-B 0.5mg/kg/day IV x 14-21days
 Cryptococcal Meningitis
• The causative organism is cryptococcus neoformans

• HIV-infected children between 6-12 years of age with severe immunosuppression are at
risk of getting infected
• However, occurrence is less among HIV-infected children than it is in adults

• Incidence has reduced with the scale up of ART program

Clinical manifestations:
• Presents as acute or sub acute meningitis or encephalitis

• Fever, headache, malaise & altered mental status

• Neck stiffness & focal deficits are rare

 Diagnosis of Cryptococcal Meningitis
• Based on a high index of suspicion and presence of signs of raised Intra- Cranial
Tension(ICT), it is suspected that the child has cryptococcal meningitis
• Diagnosis is by lumbar puncture and CSF studies, after excluding papilledema
• The opening pressure of the CSF is elevated
• India ink staining of CSF shows budding yeast
• Cryptococcal antigen can be detected by latex agglutination test in:
• CSF or
• serum
• Fungal cultures from blood and sputum can identify the organism
 Recap of CSF Findings in different neurological Infections
Neurological
Infection Cells Biochemistry Microbiology

Protein elevated(30- India ink staining positive

Cryptococcal Lymphocytic, may be 150mg/deciliter) Cryptococcal antigen(CrAg) test positive
meningitis normal Low Sugar Organism isolated by Sabouraud
(50-70mg/decilitre) Dextrose Agar(SDA) culture

Predominantly
Protein elevated(40-
Tuberculous Lymphocytic, Isolation of M tuberculosis in CSF
100mg/decilitre)
(TB)Meningitis A few hundred CBNAAT & culture - occasionally positive
WBCs/micro-litre Low to normal Sugar

Protein very high

Predominantly
(>100mg/decilitre), Gram’s stain and Routine culture may
Pyogenic meningitis Neutrophilic, > 1000
Very Low reveal the organism
WBCs/micro litre
Sugar(<40mg/decilitre)

* Lumbar puncture to be done after ruling out papilloedema

 Management of Cryptococcal Meningitis in CLHIV
Induction: A short-course (two-week) induction with preferred regimen:
Preferred regimen:
• Amphotericin B deoxycholate (1mg/kg/day) and Flucytosine (25 mg/kg QID) for one week
•followed by one week of high dose Fluconazole (12mg/kg/day, max dose of 800mg daily)
Alternative options:
• Two weeks of fluconazole (12 mg/kg/day, max dose 800 mg daily ) + Flucytosine (25 mg/kg QID)
OR
• Two weeks of Amphotericin B deoxycholate (1mg/kg/day) + Fluconazole ( 12 mg/kg/day, max
dose 800 mg daily )
• Patients treated with amphotericin B should be monitored for dose-dependent nephrotoxicity
and electrolyte disturbances.
Routine use of adjunctive corticosteroid therapy during the induction phase is not recommended
in treating HIV-associated cryptococcal meningitis
WHO Guidelines for the diagnosis, prevention and management of Cryptococcal disease in HIV-infected adults, adolescents
and children -March 2018. https://apps.who.int/iris/bitstream/10665/260399/1/9789241550277-eng.pdf?ua=1
 Treatment of Cryptococcal Meningitis in CLHIV
CONSOLIDATION PHASE MAINTENANCE PHASE (Secondary Prophylaxis)

TIME OF After completion of 2 weeks of After completion of 10 weeks of treatment (2 weeks of

STARTING Induction therapy Induction and 8 weeks of Consolidation Therapy)

REGIMEN Fluconazole Fluconazole

(Itraconazole is associated with significantly higher
relapse rate)
DOSE 6–12 mg/kg/day 6 mg/kg/day for children
(maximum dose of 800 mg daily) (maximum dose of 200 mg daily)

DURATION For eight weeks following the To be continued till

induction phase - Patient is adherent to ART
- CD4 cell ≥ 100 cells/cmm
- Viral load is suppressed (<1000 copies/ml)
- To be given for at least 1 year

WHO Guidelines for the diagnosis, prevention and management of Cryptococcal disease in HIV-infected adults, adolescents
and children -March 2018. https://apps.who.int/iris/bitstream/10665/260399/1/9789241550277-eng.pdf?ua=1
Cryptococcal Meningitis: Treatment Follow up
Assess response to therapy:
• A repeat Lumbar puncture should be performed before consolidation phase
is initiated
• Evidence of clinical improvement and a negative CSF culture on repeat LP
(done before consolidation phase is initiated) indicate a good response to
therapy
• Cryptococcal antigen titres in CSF can also measure response to therapy
• A CSF titre of > 1:8 after completion of therapy indicates treatment failure or
relapse
• For raised intracranial pressure, repeated lumbar punctures are performed
• Corticosteroid and acetazolamide should not be used to reduce intracranial
pressure
Talaromycosis (previously known as Penicilliosis)
Images Courtesy: CoE, RIMS,
Imphal, Manipur
• Talaromycosis is caused by Taloromyces
marneffei, a dimorphic fungus
• Endemic in north eastern parts of India
(Manipur)
• It is one of the AIDS defining opportunistic
infections (WHO Stage 4 disease)
• Clinical features:
• Fever
• lymph node & hepatic involvement
possible
• May present as disseminated disease in
severely immunocompromised children
• Skin lesions:
• papular rash with central umbilication.
similar to Molluscum
 Treatment of Talaromycosis

• Disseminated Talaromycosis is fatal if untreated

• Three phases of treatment:

• Induction phase :Amphotericin B: 0.6mg/kg/day IV x 2weeks

• Consolidation phase: Oral Itraconazole 2-5mg/kg/day for 10 weeks

• Maintenance phase(secondary prophylaxis):

• Itraconazole 2-5mg/kg/day orally until CD4 count increased to >200 CD4

cells/mm3after ART initiation and is sustained for at least 6 months

• Relapse is common in Talaromycosis

 Key Points
• Common Opportunistic Infections associated with HIV infected children are bacterial,
fungal, viral & protozoal
• Recurrent bacterial infections especially Pneumonias are common in HIV infected
infants and young children
• Suspect PCP in a CLHIV with cough, tachypnoea and signs of respiratory distress;
steroids should be used in severe PCP
• Candida albicans is the most common among fungal infection in children of which
Oropharyngeal Candidiasis or thrush is the commonest
• Cryptococcal meningitis occurs less frequently in children and requires prolonged
treatment
• Secondary prophylaxis is given to a child with history of previous cryptococcal disease.
• Talaromycosis (previously known as Penicilliosis) is endemic in North-Eastern part of
India and it is one of the AIDS-defining OIs
Thank You