Case 1: The formula dance

A five-month-old boy presented with a two-month history of nonproductive cough and mild nasal congestion. There was no history of fever, vomitting or diarrhea. The infant was feeding well until a few days before presentation when the mother noticed that he exhibited decreased appetite and was less active. He had normal bowel movements and urine output, and the rest of his review of systems was unremarkable. He was breastfed at birth and occasionally received supplementation with cow’s milk formula. At two months of age, he was exclusively fed with cow’s milk formula. He subsequently developed constipation with some blood-tinged stools and was switched to a soy-based formula. This formula resulted in significantly looser stools and the diagnosis of cow’s milk protein allergy was entertained. He was then switched to a partially hydrolyzed formula, which he seemed to tolerate well. At the age of three months, he had fallen below the 3rd percentile for growth and was being followed closely by his paediatrician for failure to thrive. There was no history of any previous infections. His family history was noncontributory. His physical examination revealed an infant who appeared chronically unwell but was not in acute distress. His weight was 4.76 kg (below the 3rd percentile). He appeared pale and emaciated, had a heart rate of 182 beats/min and a respiratory rate of 84 breaths/min. His oxygen saturation was above 98% on room air and he was afebrile. He had moist mucous membranes and no oral thrush was seen. He had multiple, enlarged, mobile, fluctuant cervical lymph nodes bilaterally, with some overlying skin erythema, as well as palpable inguinal lymphadenopathy. Respiratory and cardiovascular examinations were normal. His abdomen was soft, but he became fussy during the examination. The liver edge was palpable at 3 cm below the costal margin and the spleen tip was palpable at 2 cm below the costal margin. His skin was diffusely dry and eczematous. A chest radiograph revealed a possible right upper lobe infiltrate. An initial set of laboratory investigations showed a hemoglobin level of 79 g/L, a white blood cell count of 25.5×109/L with a neutrophil count of 17.6×109/L and a platelet count of 609×109/L. Electrolytes and creatinine levels were normal. He had an albumin level of 22 g/L. His liver enzymes and coagulation profile were normal. An ultrasound of the cervical chains revealed enlarged lymph nodes and bilateral cervical abscesses. An abdominal ultrasound revealed multiple hepatic abscesses and mild splenomegaly. The infant underwent a full immunological evaluation. His lymphocyte immunophenotyping was normal. He had elevated levels of immunoglobulin (Ig) G (18.1 g/L), IgA (3.6 g/L), IgM (2.1 g/L) and IgE (155 g/L). An additional test confirmed the diagnosis. Using the dihydrohodamine test, our patient was found to have a neutrophil oxidative burst index of 1.18 (normal 32 to 3000). Aspirates of a cervical neck abscess and liver abscess grew Staphylococcus aureus. Blood cultures and bronchoalveolar lavage were sterile. The patient was placed on broad-spectrum intravenous antibiotics, and subsequently changed to intravenous cloxicillin and rifampin for targetted and synergistic action against S aureus. Itraconazole was initiated for fungal prophylaxis. The infant was placed on total parenteral nutrition for caloric support. An eventual challenge with cow’s milk formula while on antimicrobial therapy demonstrated that the infant tolerated this formula. Chronic granulomatous disease (CGD) is a condition characterized by the phagocyte’s inability to destroy certain microbes. This defect is caused by a mutation of the phagocyte NADPH oxidase cytochrome gene (1), the respiratory enzyme responsible for generation of reactive oxygen species. These reactive oxygen species serve to activate proteases that are responsible for the neutrophil’s bacteriocidal activity (2). A defect in this enzyme complex leads to the inability to kill catalase-positive organisms, predisposing the individual to recurrent, life-threatening bacterial and fungal infections. The five most common organisms causing infection in CGD patients are S aureus, Burkholderia cepacia complex, Serratia marcescens, and Nocardia and Aspergillus species (3). There are five types of CGD, each associated with a mutation in the NADPH oxidase complex. CGD is more common in boys, reflected by the fact that the X-linked form accounts for 65% of cases. Each mutation carries a certain degree of severity, thus, affecting the average age of presentation. The majority of patients are diagnosed before five years of age (4). The present case describes a male infant who presented typically with vague, nonspecific symptoms and failure to thrive, which should raise suspicion of a pathological underlying cause such as an occult systemic infection. Careful and thorough physical examination may yield signs of occult infection, especially in a nonverbalizing infant, in whom symptoms are difficult to elicit and clinical signs become key. Gastrointestinal manifestations, along with physical findings, such as hepatosplenomegaly, lymphadenitis and abnormal wound healing, are all clues that should prompt further immunological investigations (3). In one review, gastrointestinal symptoms in the first decade of life were present in 70% of patients, and 33% had documented involvement of the gastrointestinal tract (5). The most common complaint was diarrhea, followed by abdominal pain, nausea, vomitting and constipation. Patients also present with recurrent infections, the most common being pneumonia (80%), followed by suppurative adenitis (60%), hepatic abscess (25% to 50%) and osteomyelitis (25%) (6). Unlike typical abscesses, these are often multiple, small, granulomatous abscesses with dense surrounding granulation tissue (7). The initial diagnostic test of choice is the dihydrorhodamine test for determining neutrophil function, the result of which is reported as a neutrophil oxidative burst index. The final diagnosis of CGD requires a confirmatory genetic test, which is important in risk profiling of the X-linked form. Our patient was found to have the X-linked mutation and his mother was found to be a carrier. Although CGD was once a fatal disease during childhood (life expectancy of 12 years), better understanding of the nature of the illness and early detection has led to significant improvement in prognosis. Initial management is directed at aggressive treatment of documented infections, caloric supplementation and life-long prophylaxis. Combination trimethoprim-sulfamethoxazole and itraconazole in therapy has been shown to dramatically reduce the rate of severe infections (8). Furthermore, it has long been recognized that children with immunodeficiencies fare worse when they are malnourished. Caloric needs can be accurately determined by indirect calorimetry to address the increased metabolic demand (9). The definitive cure for CGD remains hematopoietic cell transplantation (8), which will be performed in the child presented here. Although other etiologies may be more common, primary immunodeficiency should be considered when an infant presents with severe failure to thrive and gastrointestinal complaints. Immunodeficiencies can sometimes lead to occult rather than frank infections, presenting as nonspecific symptoms; rapid diagnosis can prevent life-threatening complications. Immunodeficiency disorders may still be possible even in the presence of high neutrophil counts and high Ig levels. Early, life-long prophylactic treatment with combination trimethoprim-sulfamethoxazole and itraconazole therapy has been shown to dramatically reduce the rate of severe infections in patients with CGD.

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