Patient 1

Patient 1, a 13-year-old girl with refractory So-JIA who was previously reported with osteoarticular tuberculosis while treated with etanercept (12) (Table 1), never achieved complete disease control (Juvenile Arthritis Disease Activity Score [JADAS]–10 score 25–30) (Table 1) (13). She was assessed for HSCT on February 17, 2004 (Table 2). After CVC insertion for treatment with weekly intravenous methylprednisolone pulses (IVMPs) and 1 dose of infliximab, routine CVC cultures grew fully sensitive coagulase-negative Staphylococcus. She was treated with systemic teicoplanin and vancomycin locks to all 3 CVC lumens for 7 days (15). On February 28, three days after antimicrobial treatment ended, she was readmitted with fever (40°C), generalized macular erythematous rash, abdominal discomfort, nausea, vomiting, and diarrhea. Alongside empirical treatment with systemic antimicrobial drugs (vancomicin and cefotaxime) and intravenous fluids, presumed adrenal insufficiency was treated with hydrocortisone, but she remained febrile (38.6°C); on February 29, she had a sudden episode of hypotension (blood pressure 70 mm Hg) requiring fluid bolus resuscitation and further hydrocortisone. On March 1, as the CVC was accessed for administration of antimicrobial drugs, she became pale and light-headed and collapsed; the CVC was removed, but she died of cardiorespiratory arrest. Multiple peripheral blood and CVC cultures taken during this period remained sterile. Autopsy showed congested lungs and pleural effusions, atrophic adrenal glands, no identifiable thymus, and no erythrophagocytosis in liver or spleen. Cultures from the CVC tip, both lungs, and the pleural fluid samples taken post mortem grew α-hemolytic Streptococcus.

Patient 2

Patient 2, a 6-year-old girl, had refractory So-JIA (Table 1) with macrophage activation syndrome (MAS), a form of hemophagocytic lymphohistiocytosis and a potentially fatal complication characterized by unremitting fever, pancytopenia, liver failure with coagulopathy, and central nervous system dysfunction (14). Several months before referral, she was brought for care again with possible MAS; symptoms and signs included fever, hepatomegaly, diarrhea, anemia, thrombocytopenia, high serum ferritin (5,670 μg/L [reference 20–60 μg/L]), albeit with leukocytosis and normal clotting (16). She was treated with IVMP and high-dose intravenous immunoglobulin. A previously inserted CVC was removed because of Enterobacter intermedius infection. Because her disease was never in full remission (JADAS-10 score 20–30; Table 1), she was referred on May 27, 2004, for HSCT (Table 2). On June 1 (one week after new CVC insertion), she was admitted with fever (38°C), macular erythematous rash, vomiting, swelling and pain of several joints, and cough (Table 2). Chest examination and radiographic findings were normal, and she was treated empirically with systemic antimicrobial drugs (teicoplanin and meropenem) for 1 week (15) and a 3-day course of IVMP for presumed MAS. After transient improvement during the next few days, on June 6 the child again became unwell, with fever (38.5°C), rash, hepatomegaly, and joint pain (Table 2). Empirical treatment with systemic antimicrobial drugs (teicoplanin and ceftriaxone) was restarted with another 3-day course of IVMP, but she remained febrile (38.5°C) and became restless with abdominal pain and vomiting. She was transferred to the pediatric intensive care unit (PICU), where surgical reasons for acute abdomen pain were excluded. Ciprofloxacin and ambisome were added to the treatment regimen, but the child’s condition rapidly progressed into multiorgan failure (Table 2), and she died on June 10. Multiple peripheral blood and CVC cultures taken during this period remained sterile. The family did not agree to autopsy. Culture from the CVC tip removed postmortem grew coagulase-negative Staphylococcus.

Patients 3 and 4

Both children received immunosuppressive conditioning with anti–T-cell globulin (rabbit, 10 mg/kg), fludarabine (150 mg/m²), and cyclophosphamide (120 mg/kg) (10,11). Both died during T-cell–depleted (by CD34+ positive selection; Miltenyi Biotec, San Diego, CA, USA) autologous HSCT.

Treatment with Combined DMARDs, Including Biologicals

At death, patients 1 and 2 had active disease treated with high-dose systemic corticosteroids and methotrexate; they previously had been exposed to long-term and multiple DMARDs, including anti–TNF-α biologicals (Table 1). Patients 3 and 4 underwent autologous T-cell–depleted HSCT after a severely immunosuppressive conditioning regimen.

Clinical observation of increased risk from severe infections in children with JIA, often requiring treatment in a hospital (17), recently was confirmed in a study of a large JIA cohort (18). The increased risk for concurrent immunosuppressive therapy, in addition to the underlying disease-related immune dysfunction (8,17), was supported by this study, in which high-dose systemic corticosteroids, but not methotrexate and/or anti–TNF-α agents, substantially increased susceptibility to severe infections (18). Although simultaneous use of different biological DMARDs is not common (5,6), a recently published study highlighted the exposure to multiple and often combined immunosuppressive drugs, such as corticosteroids, methotrexate, cyclosporine, cyclophosphamide, and a variety of biological antiinflammatory DMARDs, including TNF-α, IL-1, and IL-6 blocking agents, as a major risk factor for severe infections and the unusually high rate of death for a selected group of children with refractory So-JIA, often complicated by MAS, and associated with pulmonary hypertension, interstitial lung disease, and alveolar proteinosis (19). It is well recognized that severe immunosuppression targeting B- and/or T-lymphocyte functions (e.g., B-cell–depleting agents, such as rituximab, T-cell activation blocking agent abatacept, anti-CD52 monoclonal antibody alemtuzumab, HSCT procedure) is often complicated with infections caused by a wide spectrum of pathogens, such as pyogenic bacteria, viruses, and fungi (7,9–11). In contrast, blocking specific inflammatory pathways (e.g., IL-1, IL-6, TNF-α) mimics some of the very rare primary immunodeficiencies of the innate immune system (20), with susceptibility to a relatively narrow range of pathogens (21,22). Infections with encapsulated pyogenic bacteria have been reported in patients with deficiencies of IL-6 function (23), whereas the essential role of TNF-α in defense against intracellular pathogens (24) was highlighted by the initially observed increased risk for mycobacterial infections associated with anti–TNF-α biologicals (7,12), prompting the introduction of effective screening and prevention measures (24). Although inconsistently reported (25), unusually prolonged, severe, and life-threatening infections with common bacterial pathogens are being seen in children with JIA treated with combined DMARDs, including anti–TNF-α agents (26,27). As observed in these patients (23,28), because of blocking of the inflammatory response mediated by TNF-α, IL-1, or IL-6 cytokines, these patients might not have high fever and raised CRP, a fact of which clinicians should be aware (20–24,29). Regardless of active disease and combined immunosuppressive therapy, patients 1 and 2 (i.e., those not undergoing HSCT) had preserved inflammatory responses (Table 2) and appropriate routine immunologic testing (data not shown).

CVC-Related Bacterial Infections

Three patients died of CVC-related bacterial sepsis with α-hemolytic Streptococcus and coagulase-negative Staphylococcus, common and fully sensitive organisms, despite timely administered appropriate antimicrobial therapy (15). Long-term CVCs are essential for patients requiring frequent blood tests and intravenous treatments. Unfortunately, CVC-related bloodstream infection is a well-recognized and potentially severe complication. Coagulase-negative Staphylococcus species are the most common pathogens causing CVC-related infections. Guidelines recommend treatment with 10–14 days of systemic antimicrobial drugs and antibiotic locks, but routine CVC removal is not recommended because most patients have a benign course and rarely develop sepsis or poor outcome (15). S. aureus, enteric gram-negative bacilli and Candida are less frequent but potentially more severe pathogens. Coagulase-negative Staphylococcus species (S. epidermidis in particular) were the most common (>50%) pathogens identified from 146 episodes of bacteremia in 64 children with primary immunodeficiencies undergoing HSCT in Great North Children’s Hospital, whereas Enterococcus species, gram-negative organisms, and Candida were isolated only in few cases each (30). Most (80%) episodes were successfully treated with appropriate systemic and antibiotic locks; CVC was removed in 12 patients, and the only death resulted from overwhelming C. albicans infections despite CVC removal (30). Contrary to that study, severe and life-threatening CVC-related sepsis caused by S. epidermidis has been reported in a significant percentage of children with systemic vasculitis treated with infliximab and combined immunosuppressive and/or antiinflammatory therapies (31). Two deaths from CVC-related sepsis resulting from coagulase-negative Staphylococcus and combined Escherichia coli and Candida infection were reported from a cohort of children with inflammatory bowel disease treated with adalimumab in combination with other immunosuppressive medications (32). This high risk for severe CVC-related infections associated with active disease that requires multiple immunomodulatory therapies was also reported from a group of children with pediatric rheumatic disease–related complications admitted to PICU, with substantially high rate of death (50%), of which 44% resulted from multiorgan failure (33).

MAS versus Multiorgan Failure

Because the 3 patients we describe who died of CVC-related bacterial sepsis manifested unusually severe and rapidly progressing multiorgan failure, we considered the possibility of MAS in the differential diagnoses (14,16,33,34). MAS is a well-recognized major risk factor for death in children with JIA admitted to PICU (33,34). A recent international study of a large cohort of So-JIA patients identified the most common clinical features as fever, organomegaly, central nervous system involvement, and hemorrhage (16). The most useful laboratory parameters were thrombocytopenia; hyperferritinemia; increased liver transaminases, lactate dehydrogenase, triglycerides, and D-dimer levels; and decreased leukocyte count, erythrocyte sedimentation rate, and fibrinogen (16).

Some features that manifested near death, such as persisting fever, falling neutrophil and platelet counts, and increased serum transaminase levels (Table 2; patient 1 on March 1) suggest MAS in patient 1 (16). Unfortunately, not all of the laboratory parameters highlighted as essential for the clinical diagnosis of MAS were available (14) (Table 2). However, the fact that she collapsed after CVC was accessed and that α-hemolytic Streptococcus grew from the CVC line tip, lung tissue, and pleural effusion samples after death favors infection as the cause of death. In patient 2, persisting fever, hepatomegaly, and high serum ferritin level suggested MAS, but increasing platelet and neutrophil counts, erythrocyte sedimentation rate, and fibrinogen and normal liver transaminase levels did not support MAS (14) (Table 2; patient 2 on June 6). Although rapid deterioration to terminal multiorgan failure was associated with falling platelet count, deranged liver function, and clotting (Table 2; patient 2 on June 10), the high neutrophil count suggested overwhelming fungal infection (which cannot be ruled out because autopsy was not performed), regardless of negative fungal cultures. In patient 4, unusually severe, progressive multiorgan failure developed after CVC-related sepsis, but normal liver function results and clotting and adequate CRP response did not support MAS. Features of macrophage activation in bone marrow biopsy were seen later in the course of progressive multiorgan failure and in parallel with unusual hyperinflammation, suggesting possible fungal infection. However, multiple cultures from different sites remained negative, and autopsy confirmed severe pancreatitis. In patient 3, disseminated adenovirus and EBV infection/reactivation during HSCT led to bone marrow aplasia. In the terminal stage of multiorgan failure with A. fumigatus infection, results of liver function and clotting tests were normal, and inflammatory markers were raised (erythrocyte sedimentation rate 80 mm/h [Westergren method; reference 1–10 mm/h]; CRP 200 mg/L [reference 0–5 mg/L]; ferritin 11,000 μg/L [reference 20–60 μg/L]).