Eight month old boy with recurrent infections

Patient presentation

An eight month old boy presented with failure to thrive and recurrent infections including dissemination of his BCG vaccination. HIV ELISA test was negative.

Acknowledgement
This case study was kindly provided by Dr Monika Esser MMed Paed, Head of Division of Immunology, N.H.L.S Coastal Branch, Tygerberg Hospital.

History

8 months old

• Child presented with failure to thrive, recurrent infections and dissemination of his BCG vaccination he received at birth.
• Blood tests showed a severe lymphopaenia which was confirmed by abnormal lymphocyte subsets and severely diminished mitogen proliferation.
• He had received all vaccinations up to this point with positive IgG antibodies present. – Expanded Programme on Immunisation (EPI) schedule
• HIV ELISA test was repeated and found to be negative.
• He was given the likely diagnosis of severe combined immunodeficiency disorder or SCID.
• The variable Immunoglobulin levels were presumed to be of maternal origin.
• The patient was isolated and barrier nursed on a standard SCID protocol and treated for disseminated BCG infection.

10 months old

• The mother was screened as a possible donor for bone marrow transplant, she tested HIV (+).
• PCRfor HIV was done on the patient and he was found to be HIV (+).
• He was started on HAART therapy, 2 months after starting treatment for BCG dissemination.

16 months old

• After 6 months of HAART the patient’s lymphocyte profile and mitogen responses normalised.
• Immunoglobulin levels rose to normal and remained at normal levels.
• Viral load was undetectable.
• He experienced no further serious infections, and remained HIV ELISA (-) at one year follow- up.

Important to note:  

• A subsequent review of his hospital records revealed a previous admission with PCP pneumonia under a different birth date and registration number at 4 months of age.
• At the time he had a positive HIV PCR result. He was then lost to follow up until the admission at 8 months of age.
• Moderate lymphopaenia was noted at the 4 month admission.

Differential Diagnosis

• SCID
• Bone Marrow suppression
• HIV

Also consider causes of false-negative HIV antibody ELlSA:

• Acute or early HIV infection (pre-seroconversion)
• Late stage HIV disease – seroreversion (severe immunodeficiency)
• Unusual HIV strain (HIV-1 group N, O or recombinant or certain HIV-2 strains)
• Immune complex formation
• Rheumatoid factor
• Severe combined immunodeficiency (SCID)
• B-cell disorder (agammaglobulaemia, common variable immunodeficiency)
• Immunosuppressive therapy
• Replacement transfusion
• Bone marrow transplant
• Laboratory glove starch powder
• Laboratory error

Examination

Ill looking child, severely malnourished.
Patient is failing to thrive, marasmic, measuring below the 5th centile for height and weight.

On General:

• Respiratory rate- 30 breaths per minute
• Temperature- 38°C
• Generalised lymphadenopathy

Respiratory Examination:

• Persistent productive cough
• Harrison’s sulcus
• Bilateral lower lobe crepitations

Other systems:
Nil of note

Investigations

Phytohaemagglutinin (PHA) stimulates predominantly T-helper cell activity

Concanavalin A stimulates predominantly T-suppressor cell activity

Protein A stimulates B-cells.

(in acknowledgement of NHLS-Tygerberg Hospital)

Discussion

There are two discussion parts to this case. Although the child does not have SCID as was initially thought we have included SCID in the first part of the discussion.

• Combined Immunodeficiencies (CID’s) are characterized by defects in T-cell development and/or function which may be associated with abnormalities in the development of B and/or Natural Killer (NK) lymphocytes.
• Patients with SCID have the most severe form of T-cell depletion.
• Severe early onset infections, including uncontrolled BCG infection and growth failure are characteristic. Without early diagnosis and proper treatment including bone marrow transplantation most patients die within the first year of life.
• Even in normal fetuses and neonates T-cell function is impaired compared to adult functioning. This includes T-cell mediated cytotoxicity and T-cell help for B-cell differentiation.
• Some of the inhibitory effects of HIV-1 infection on the immune system  may even occur in HIV-exposed, but uninfected infants.
• In the early days of Paediatric HIV infections, prior to specific antibody testing, primary immunodeficiencies (PID) were included in the differential diagnosis of the recurrent infections observed. In this child the unfortunate duplication of hospital records led to an incorrect initial diagnosis of PID.
• The recovery of  lymphocyte numbers and function on HAART confirmed the diagnosis of an acquired immunodeficiency.
• The persistence of a negative HIV ELISA, with high viral loads and (+) PCR’s
• once the immune response had normalised may have been due to bone marrow suppression or infection in utero (i.e. mother seroconverting before delivery). But these are speculative answers and remain to be explained.
• False negative ELISA’s have been reported in situations of severe CD4 depletion, possibly reflecting a subnormal antibody response.

The most likely hypothesis in this case is the following:

• The mother had a primary HIV-1 infection during pregnancy most probably in the third trimeseter.
• The child was infected perinatally before maternal seroconversion.
• Hence, no placental transfer of maternal HIV-1 antibodies. (Also child is not breastfed or breastfeeding stops before seroconversion.)
• Severe immunodeficiency results in child due to HIV infection, hence no antibody response can be mounted.
• Mother is tested after seroconversion and is now ELISA pos.
• Child is HIV+ by PCR but not by ELISA (no antibodies present).
• ARV treatment reduces viral load to below detection, lymphocyte responses appear normal.
• Subsequent ELISA testing remains negative due to lack of HIV antigen.

Treatment

Patient was treated with HAART and continued to see improvements. His viral load remained undetectable and his CD4  count continued to improve.

Final Outcome

Although patient has remained ELISA negative, he still remains PCR positive for HIV and has therefore remained HIV positive.

It is important to educate the family on this fact because they must understand that if they test their child for HIV at another facility they may be told that their child is HIV negative based on the ELISA test. However, their child is HIV positive and they must therefore not stop the ARVs, if they do there will be a resurgence of symptoms.

Evaluation – Questions & answers

What is the likely cause of this child having a negative ELISA in the face of a positive HIV PCR?

What is the importance of the Lymphocyte Proliferation Assay?

How do infants develop disseminated BCG?

How is disseminated BCG avoided?

What was the 1st generation HIV antibody ELISA test designed to detect?

What was the 2nd generation HIV antibody ELISA test designed to detect?E

What was the 2nd generation HIV antibody ELISA test designed to detect?

What was the 3rd generation HIV antibody ELISA test designed to detect?

What was the 4th generation HIV antibody ELISA test designed to detect?