ISSN 0973 - 9289

HIV and Clinical Manifestations

HIV Diagnosis

?Pediatric HIV primarily is a vertically transmitted infection with over 80% of the patients acquiring HIV through this route. Children infected pertinently with HIV vary greatly in how rapidly they develop immune suppression and symptoms or signs of disease. Systemic and pulmonary findings were common in the first HIV infected children who presented in the USA and in Europe; whereas chronic Diarrhea, wasting and severe malnutrition are predominant presentations in Africa. In India, common clinical presentations are hepatosplenomegaly, lymphadenopathy, tuberculosis, failure to thrive, chronic dermatitis, pyrexia of unknown origin, recurrent respiratory tract infections, chronic otitis media and chronic Diarrhea.

Clinical presentation in Infants

Among the early manifestations of HIV in children reported are HIV encephalopathy & opportunistic infections especially with pneumocystis jiroveci (PCP), Cytomegalovirus (CMV), respiratory viruses and bacterial pneumonia. Recurrent gastrointestinal infections and oral thrush are commonly found. Lymphadenopathy, splenomegaly and hepatomegaly often are seen in the 1st year of life. Up to 10% of infants presenting with HIV have severe developmental delay and encephalopathy.

Rapid progressors

Few infants (15-25% infected newborns in developed countries) may develop AIDS within the first few months of life and if left untreated they have a median survival time of 6-9 months. Opportunistic infections and neurological complications are features seen more commonly in this group. These are the children that are infected intra-uterine with most of them showing positive HIV-1 culture and/or detectable viral load (median level 11,000copies/ml) in blood in the first 48 hr of life.

Long-term non-progressors (LTNP)

5–15% of HIV-infected individuals do not experience clinical or immunological progression despite a long duration of infection in the absence of HAART. They are known as long term non-progressors. They maintain good CD4 counts and tend to have low viral loads. Elite controllers (EC) are those who constitute <1% of HIV-infected individuals who maintain undetectable viral loads (<50 copies/mL) in the absence of HAART. EC generally have very slow disease progression, with some infected for 25 years without signs of AIDS.

Clinical Presentation in children

Growth failure, fever, Diarrhea and secondary infections are seen beyond infancy. Many children who present with HIV may have had mild symptoms for many years. They may present with recurrent ear infections with sinusitis, chronic parotitis, chronic otitis media, nail fungal infections and molluscum contagiosum. Hepatosplenomegaly and lymphadenopathy persist.

HIV in older children

Older children have growth failure, delayed puberty and subtle cognitive dysfunction. Systemic manifestations such as HIV cardiomyopathy, idiopathic thrombocytopenic purpura (ITP) are seen in older children and adolescents.

HIV Disease Classification

1994 Revised CDC Classification (Table 1)

For the simplification of management of HIV infected children, Center for Diseases Control and Prevention in 1994 categorized HIV in children < 13 years of age into 4 groups: N, A, B and C based on signs, symptoms, or diagnoses related to HIV infection. Category N, not symptomatic, includes children with no signs or symptoms considered to be the result of HIV infection or with only one of the conditions listed in Category A, mildly symptomatic. Category N was separated from Category A partly because of the substantial amount of time that can elapse before a child manifests the signs or symptoms defined in Category B, moderately symptomatic. Category B includes all children with signs and symptoms thought to be caused by HIV infection but not specifically outlined under Category A or Category C, severely symptomatic. Category C includes all AIDS-defining conditions except lymphoid interstitial pneumonitis (LIP).

Table 1: 1994 Revised CDC clinical categories of HIV in children <13 years

CATEGORY N: NOT SYMPTOMATIC

Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in Category A.

CATEGORY A: MILDLY SYMPTOMATIC

Children with two or more of the conditions listed below but none of the conditions listed in Categories B and C.

Lymphadenopathy (>=0.5 cm at more than two sites; bilateral = one site)
Hepatomegaly
Splenomegaly
Dermatitis
Parotitis
Recurrent or persistent upper respiratory 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. Examples of conditions in clinical Category B include but are not limited to:

Anemia (<8 gm/dL), neutropenia (<1,000/mm3), or thrombocytopenia (<100,000/mm3) persisting >=30 days
Bacterial meningitis, pneumonia, or sepsis (single episode)
Candidiasis, oropharyngeal (thrush), persisting (>2 months) in children >6 months of age
Cardiomyopathy
Cytomegalovirus infection, with onset before 1 month of age
Diarrhea, recurrent or chronic
Hepatitis
Herpes simplex virus (HSV) stomatitis, recurrent (more than two episodes within 1 year)
HSV bronchitis, pneumonitis, or esophagitis with onset before 1 month of age
Herpes zoster (shingles) involving at least 2 distinct episodes or more than one dermatome
Leiomyosarcoma
Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex
Nephropathy
Nocardiosis
Persistent fever (lasting >1 month)
Toxoplasmosis, onset before 1 month of age
Varicella, disseminated (complicated Chickenpox)

CATEGORY C: SEVERELY SYMPTOMATIC

Serious bacterial infections, multiple or recurrent (i.e., any combination of at least two culture-confirmed infections within a 2-year 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 month
Cytomegalovirus disease with onset of symptoms at age >1 month (at a site other than liver, spleen, or lymph nodes)
Encephalopathy (at least one of the following progressive findings present for at least 2 months in the absence of a concurrent illness other than HIV infection that could explain the findings): a) failure to attain or loss of developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychological tests; b) impaired brain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophy demonstrated by computerized tomography or magnetic resonance imaging (serial imaging is required for children <2 years of age); c)acquired symmetric motor deficit manifested by two or more of the following: paresis, pathologic reflexes, ataxia, or gait disturbance
Herpes simplex virus infection causing a mucocutaneous ulcer that persists for >1 month; or bronchitis, pneumonitis, or esophagitis for any duration affecting a child >1 month of age
Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar lymph nodes)
Kaposi's sarcoma
Lymphoma, small, noncleaved cell (Burkitt's), or immunoblastic or large cell lymphoma of B-cell or unknown immunologic phenotype
Lymphoma, primary, in brain
Mycobacterium tuberculosis, disseminated or extrapulmonary
Mycobacterium, other species or unidentified species, disseminated (at a site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
Pneumocystis carinii pneumonia
Progressive multifocal leukoencephalopathy
Salmonella (nontyphoid) septicemia, recurrent
Toxoplasmosis of the brain with onset at >1 month of age
Wasting syndrome in the absence of a concurrent illness other than HIV infection that could explain the following findings: a) persistent weight loss >10% of baseline OR b) downward crossing of at least two of the following percentile lines on the weight-for-age chart (e.g., 95th, 75th, 50th, 25th, 5th) in a child >=1 year of age OR c) <5th percentile on weight-for-height chart on two consecutive measurements, >=30 days apart PLUS a) chronic Diarrhea (i.e., at least two loose stools per day for >30 days) OR b) documented fever (for >=30 days, intermittent or constant)

World Health Organization (WHO) staging system for HIV in children

In 1986, WHO developed a provisional clinical AIDS case definition for adults and children to report AIDS cases in resource-constrained settings. It was modified in 1994 to accommodate 1993 revisions to European and United States Centers for Disease Control and Prevention definitions. Studies in African settings suggested that the original WHO clinical case definitions for AIDS in children were not very sensitive or specific. Thus, in 2006, WHO revised the clinical staging in children < 15 years of age. The clinical stage is useful for assessment at baseline (first diagnosis of HIV infection) or entry into long-term HIV care and in the follow-up of patients along with decision when to start cotrimoxazole prophylaxis and when to start antiretroviral therapy.

Table 2. WHO clinical staging of established HIV infection

HIV-associated symptoms	WHO clinical stage
Asymptomatic	1
Mild symptoms	2
Advanced symptoms	3
Severe symptoms	4

Table 3: WHO clinical staging of HIV/AIDS for children with confirmed HIV Infection

CLINICAL STAGE 1

Asymptomatic
Persistent generalized lymphadenopathy

CLINICAL STAGE 2

Unexplained persistent hepatosplenomegaly

Papular pruritic eruptions

Fungal nail infection

Angular cheilitis

Lineal gingival erythema

Extensive wart virus infection

Extensive molluscum contagiosum

Recurrent oral ulcerations

Unexplained persistent parotid enlargement

Herpes zoster

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

CLINICAL STAGE 3

Unexplained moderate malnutrition or wasting not adequately responding to standard therapy
Unexplained persistent Diarrhea (14 days or more)
Unexplained persistent fever (above 37.5°C 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 or periodontitis
Lymph node tuberculosis
Pulmonary tuberculosis
Severe recurrent bacterial pneumonia
Symptomatic lymphoid interstitial pneumonitis
Chronic HIV-associated lung disease including bronchiectasis
Unexplained anemia (<8 g/dl), neutropenia (<0.5 × 109 per litre) and or chronic thrombocytopenia (<50 × 109 per litre)

CLINICAL STAGE 4

Unexplained severe wasting, stunting or severe malnutrition not responding to standard therapy
Pneumocystis pneumonia
Recurrent severe presumed 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 tuberculosis
Kaposi sarcoma
Esophageal Candidiasis (or candida of trachea, bronchi or lungs)
central nervous system Toxoplasmosis (outside the neonatal period)
HIV encephalopathy
Cytomegalovirus (CMV) infection; retinitis or CMV infection affecting another organ, with onset at age over 1 month
Extrapulmonary cryptosporidiosis including meningitis
Disseminated endemic mycosis (extrapulmonary histoplasmosis, coccidiomycosis, penicilliosis)
Chronic Cryptosporidiosis
Chronic Isosporiasis
Disseminated non-tuberculous mycobacteria infection
Acquired HIV-associated rectal fistula
Cerebral or B cell non-Hodgkin lymphoma
Progressive multifocal leukoencephalopathy
Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy

References

Shah I. Age Related Clinical Manifestations of HIV Infection in Indian Children. J Trop Pediatr. 2005 Oct; 51(5):300-3.
Lyall H. Diagnosis, staging & clinical presentation of HIV in children. Clinical and laboratory diagnosis. Available from Tr@inforPedHIV 2011
Scarlatti G, Pediatric HIV infection. Lancet 1996;348:863-868.
Review of Opportunistic Infections and treatment in children. MMWR Dec 3, 2004 / 53(RR14); 1-63.
WHO Clinical Staging of HIV/AIDS and HIV/AIDS Case Definitions for Surveillance. Published by WHO, 2006.