CASE HISTORY

The patient was born at term by normal delivery after an uneventful pregnancy. He was the first child of non-consanguinous parents, both aged 19, with no relevant family history. He was breast fed for two weeks. His postnatal check was unremarkable, but a mild cough from birth led to several visits to the family doctor. He was first admitted to hospital at the age of 9 weeks following an apnoeic episode at home. He had a fine non-blanching rash on his arms, and was treated for presumed sepsis. However, all cultures were negative and he was well at discharge 48 hours later.

The patient next presented to his local hospital at the age of 3 months, with a four day history of fever, pallor, vomiting, and a high pitched cry. On the morning of admission he had three generalised seizures. Examination findings were of a pale, floppy, unresponsive infant with respiratory distress and poor peripheral perfusion. He had no rash, bruising, or hepatosplenomegaly. Weight and height were on the 25th and 50th centiles, respectively, but his head circumference was above the 97th centile. Intravenous antibiotics were begun, with a presumptive diagnosis of sepsis. Further fits occurred over the next 12 hours and the patient was ventilated for an emergency computerised tomography (CT) head scan, initially reported as normal. His respiratory condition deteriorated and he was transferred to the regional paediatric intensive care unit, where he required high frequency oscillatory ventilation.

Initial investigations showed normal clotting screens and biochemistry, but the lymphocyte count was only 1.8 × 10⁹/litre (normal range, 2.7–5.4). All lymphocyte subsets were reduced non-selectively. IgM was normal but IgG was low at 1.98 g/litre (normal range, 2.4–8.8), and IgA was undetectable. C reactive protein was greatly raised at 1240 g/litre. Cerebrospinal fluid examination revealed a white cell count of < 1, red cell count of 250, normal protein and glucose values, and no growth on culture. Chest x ray showed diffuse bilateral lower zone interstitial shadowing. Bronchoalveolar lavage was positive for both P carinii and CMV. Ganciclovir and high dose cotrimoxazole were begun intravenously. The patient improved over the next few days and was weaned from ventilation on day 6.

The original CT scan was reviewed and was felt to show borderline enlarged ventricles with bilateral subdural haematomas, confirmed at subsequent magnetic resonance imaging. The haematomas were surgically drained and a child protection investigation begun. There was no evidence of retinal haemorrhages, but a skeletal survey identified two rib fractures on the left side. Radiological opinion estimated the time of injury to have been 7–10 days before this admission.

LABORATORY DATA

The low total lymphocyte count, low CD4 subset, and low IgG values, associated with pneumocystis and CMV were highly suggestive of immunodeficiency. Serology and polymerase chain reaction for human immunodeficiency virus (HIV) were negative. Further immune function tests followed, specifically to exclude severe combined immunodeficiency (SCID) or other forms of T cell deficiency. T cell function tests consistently gave acceptable results, as judged by phytohaemagglutinin responses in vitro. Stimulated T cells expressed CD40 ligand normally (important in the context of “hyper-IgM” (HIGM) syndrome). Neutrophil numbers were normal. Adenosine deaminase and nucleotide phosphorylase concentrations, human leucocyte antigen (HLA) class I and II expression (on peripheral blood lymphocytes by flow cytometry), bone marrow aspirate, chromosome karyotype, DNA testing for ataxia telangiectasia, and response to tetanus immunisation were all normal/negative.

The initial lymphocytopenia and borderline low IgG resolved rapidly, and have remained normal on three year follow up (fig 1). Immunophenotyping of blood lymphocytes improved within months, to show normal numbers and percentages of T (CD3 positive) cells, B (CD19 positive) cells, and natural killer (CD56 positive) cells. IgA and IgM have been normal since 2 years of age. Thus, possible diagnoses such as HIV, SCID, and HIGM syndrome were all excluded.

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Figure 1

(A) IgG values (g/litre) and (B) absolute CD4 counts in our patient from admission at 3 months of age until the end of the three year follow up. The initial lymphocytopenia and borderline low IgG resolved rapidly, and have remained normal.

The examination of maternal serum between early pregnancy and this acute illness showed CMV seroconversion. Therefore, the patient probably acquired the infection in the late antenatal or early postnatal period.

On follow up over a period of three years, the patient shows severe developmental delay, but has been strikingly free of infection on cotrimoxazole prophylaxis. He has received all routine immunisations, omitting live vaccines. Prophylactic septrin was stopped without adverse consequence at this stage.

DISCUSSION

This patient had three major problems: P carinii infection, CMV infection, and evidence of non-accidental injury.

Pneumocystis carinii is a common infectious agent. Seroconversion can be demonstrated in most infants and small children,² but clinical disease occurs almost exclusively in the setting of immune compromise. Therefore, this infection should always trigger a search for possible HIV infection or other immunodeficiency. In this case, the search was surprisingly unrewarding. Had we missed something?

“Clinical disease occurs almost exclusively in the setting of immune compromise”

Cytomegalovirus is a relatively common congenital infection with a reported incidence of between 0.2% and 2.2% of live births.³ Transmission may occur during birth through cervical secretions, or later via breast milk. The virus has been shown to suppress immunity through a variety of mechanisms.^4,5

We postulate that CMV transiently impaired this child’s immune function and predisposed him to pneumocystis infection. Indeed, a similar case of congenital CMV complicated by pneumocystis has been described.⁶

Neither fractures, subdural haematomas, nor non-accidental injury have previously been reported in association with CMV or pneumocystis.