Dear Editor: The report by Jeena PM and colleagues highlights the need for HIV PCR testing in children with Pneumocystis jiroveci pneumonia with acute respiratory failure [1], but do not report whether primary immunodeficiency syndromes were considered in 14 of 38 retrovirus-negative children. It is worth noting from studies that survival of HIV-infected patients with Pneumocystis jiroveci pneumonia appears independent of anti- retroviral therapy, and a reflection of improvements in general intensive care facilities [2]. Consideration of the antibody-deficiency disease, hyper-IgM syndrome (X-linked HIGM, type 1 or HIGM type 3) is important among other primary immunodeficiency syndromes, as Pneumocystis jiroveci pneumonia may be the presenting feature in these children [see table for full list]. Although sophisticated diagnostic facilities are required to establish these diagnoses, features of low IgG (a universal finding), neutropenia, lymphadenopathy, splenomegaly with serious cytomegalovirus, adenovirus infections are pointers towards the possibility of HIGM. Pienaar S and colleagues have reported on the first kindred with HIGM type 1 syndrome from Cape Town, South Africa with a 100% mortality rate despite being on intravenous immunoglobulin therapy [3].

Low IgG with normal or raised IgM (or high isohaemagglutinins) is a consistent feature of HIGM, other immunoglobulin isotypes such as IgA and IgE are usually low but can be normal or sometimes even elevated. These patients are uniquely susceptible to Pneumocystis jiroveci pneumonia, and may present with IgM+ lymphomas, interstitial pneumonia, chronic diarrhoea and ascending cholangitis due to Cryptosporidium parvum, oral ulcers and hepatitis [4]. HIGM-type 1 affects boys due to CD40-ligand (CD40L, CD154) deficiency on activated T cells (gene located at Xq26-27), required for B- cell immunoglobulin class switch from IgM. HIGM-type 3 is autosomal recessive in inheritance with CD40 deficiency on B cells (gene located at 20q12-13.2). CD40L defect affects monocyte-macrophage activation increasing risk of infection with these organisms. Failure to detect CD40L on optimally activated T cells clinches the diagnosis of HIGH-type 1, but as CD40L is affected by various factors [age (neonates do not optimally express CD40L), point mutations in CD154 permit expression of non- functional protein], genetic confirmation remains the gold standard. Knowledge of the various presentations of these rare primary immunodeficiency syndromes guides testing for these conditions, and as treatment options are limited early diagnosis is vital.

Competing interests: None declared.

References: 1. Jeena PM, Bobat B, Thula SA, Adhikari M. Children with Pneumocystis jiroveci pneumonia and acute hypoxaemic respiratory failure admitted to a PICU, Durban, South Africa. Arch Dis Child. 2008; 93:545.

2. Miller RF, Allen E, Copas A, Singer M, Edwards SG. Improved survival for HIV infected patients with severe Pneumocystis jiroveci pneumonia is independent of highly active antiretroviral therapy. Thorax. 2006; 61: 716-21.

3. Pienaar S, Eley BS, Hughes J, Henderson HE. X-linked hyper IgM (HIGM1) in an African kindred: the first report from South Africa. BMC Pediatr. 2003; 3: 12.

4. Winkelstein JA, Marino MC, Ochs H, Fuleihan R, Scholl PR, Geha R, Stiehm ER, Conley ME. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). 2003; 82: 373- 84.