This article presents five clinical scenarios in which the initial manifestations of pediatric rheumatic diseases constitute life-threatening medical emergencies. It is intended as a problem-oriented guide for pediatricians to assist in the recognition of rheumatologic differentials in children presenting with critical illness and provides an approach to their initial investigation and management.
Pediatric rheumatic diseases can present with a wide spectrum of clinical illness, affecting virtually any organ in the body. Although they have the potential to cause significant morbidity and even mortality if not recognized and managed appropriately, in most situations the institution of treatment is not time critical. There are a few situations, however, in which prompt recognition and treatment is essential to preserve organ function and even life. This article provides a problem-oriented review of five such rheumatologic emergencies. Although each may occur in the context of known preexisting rheumatic disease, they may also be the initial presentation of the diseases concerned and may, therefore, be encountered by general pediatricians, intensivists, or emergency room physicians. This article does not deal with the extensive list of disease- and treatment-related complications that may occur in patients with known rheumatic illness, because although they require timely recognition and management, the patient’s prior history is likely to prompt consideration of rheumatologic differentials and involvement of a pediatric rheumatologist. It also does not deal with other conditions, such as septic arthritis and osteomyelitis, which although occasionally a diagnostic challenge – particularly in the neonate – and important to recognize and treat promptly, are rarely life threatening. The reader is referred to another article in this issue for more information on these conditions.
The objective of this article is to assist pediatricians, intensivists, and emergency room physicians in the recognition of clinical scenarios involving critically unwell children in which rheumatic diseases are an important, and in some cases the main, differential. Included is a guide to the key clinical and laboratory features that may be used to identify the relevant illness and an overview of initial treatment approaches. It is not the intention of this review to present detailed diagnostic criteria for the conditions considered, many of which are dealt with elsewhere in this issue. Similarly, although broad treatment principles are presented, the assumption is that after a diagnosis is confirmed the assistance of a physician experienced in the management of pediatric rheumatologic disease will be sought or the reader will consult a more detailed text.
The fetus or neonate with complete heart block
Neonatal lupus erythematosus with complete heart block
The diagnosis of complete atrioventricular heart block (CAVB) in the perinatal period is uncommon, with an estimated incidence of approximately 1 in 15,000 live births. As an isolated finding it is associated with the presence of transplacentally acquired maternal antibodies to Ro/SSA or La/SSB in more than 85% of cases, in a condition termed “neonatal lupus erythematosus” (NLE). Without treatment the prognosis of affected infants is guarded, with reported rates of in utero and 1-year mortality of 23% and 54%, respectively. It is important that pediatricians recognize the implications of this finding and the need for urgent assessment to confirm its cause and institution of appropriate monitoring and referrals for ongoing management.
Clinical Presentation
The development of CAVB in utero in fetuses with NLE may be preceded by second-degree heart block or may occur rapidly in the apparent absence of preceding lesser degrees of block. Onset may be at any time after 16 weeks gestation. Although most cases occur before the 30th week, fetuses remain at risk to term. Affected fetuses with lesser degrees of heart block at the time of delivery remain at risk of developing CAVB in the neonatal period and beyond.
The clinical presentation of CAVB in the fetus and neonate is with bradycardia. Complications of significant bradycardia, such as hydrops and pericardial effusion in the fetus and congestive cardiac failure in the neonate, may also be seen. Second-degree heart block also presents with bradycardia (heart rate <120 beats per minute), although of a lesser degree than CAVB. The detection of bradycardia in the fetus or neonate mandates immediate referral for assessment as to cause. The confirmation of heart block is by estimation of the PR interval using specialized echocardiographic techniques antenatally or by electrocardiogram after birth. Neonates with heart block in the setting of NLE may manifest other findings typical of the condition, which might serve as a clue to the underlying diagnosis. These include an annular skin rash, typically of the face and scalp; elevation of hepatic enzymes; and thrombocytopenia.
Approach to Investigation
The detection of isolated CAVB or lesser degrees of heart block in the fetus or neonate should prompt testing for the presence of antinuclear antibodies, specifically those against Ro/SSA and La/SSB, in maternal and neonatal serum. Found in approximately 0.5% of asymptomatic pregnant women, these antibodies are associated with a 1% to 2% risk of CAVB in the fetus in the absence of a prior affected pregnancy. This risk is increased to 15% to 20% if there is a history of a prior pregnancy complicated by fetal CAVB. In association with fetal heart block, these antibodies confirm the presence of neonatal lupus syndrome and appropriate monitoring and treatment should be instigated.
Treatment Overview
The management of fetuses with heart block has not been the subject of randomized trials and some aspects remain controversial. Fetal conduction block in NLE is thought to be the result of immune-mediated damage to the atrioventricular (AV) node. This damage results in scarring with CAVB as the end result. The suspected role of the immune system in this process raises the possibility that immunosuppression administered to the at-risk fetus might reduce AV node damage and prevent CAVB.
Based on data from observational studies it is generally accepted that treatment of the fetus using fluoridated corticosteroids, such as dexamethasone, administered to the mother has a role in the treatment of second-degree heart block. Such treatment may prevent progression to CAVB and in some cases may result in regression of the degree of block. More controversial is their use, with their potential side effects on the mother and fetus, in the management of first-degree heart block and established CAVB. This controversy has arisen because it is unclear if the former is a risk factor for the development of CAVB or if the latter is reversible.
Irrespective of whether corticosteroids are used, an essential component of the management of fetal heart block is frequent monitoring for complications of bradycardia, or for other cardiac abnormalities associated with neonatal lupus syndrome, such as endocardial fibroelastosis. Fetal heart rates greater than 55 to 60 beats per minute are usually tolerated and early delivery of the fetus is not required in the absence of other complications. Early delivery should be considered if the fetal heart rate is less than 55 to 60 beats per minute. β-Sympathomimetic agents may be used as a temporizing measure. A significant proportion of babies with CAVB require cardiac pacing after birth and delivery should be effected at a center with ready access to this capability.
Neonates who present with CAVB should be managed according to their degree of circulatory decompensation. The rate of pacemaker placement in the neonatal period is lower in this group than in those diagnosed in utero, although over the longer term the rate of both groups is similar. Neonates followed in utero with first- and second-degree heart block require ongoing follow-up because they remain at risk for the development of higher degrees of heart block over time.
The febrile child with pancytopenia
Macrophage activation syndrome secondary to:
Systemic lupus erythematosus
Systemic juvenile idiopathic arthritis
Kawasaki disease
The differential diagnosis of fever in association with pancytopenia includes such entities as sepsis, myelodysplastic syndromes, and malignancy, all of which pediatricians are familiar with and routinely work-up, treat, and refer when appropriate. Less commonly appreciated is the rheumatologic differential of macrophage activation syndrome (MAS). This potentially fatal disorder, a secondary form of hemophagoctyic lymphohistiocytosis (HLH), may complicate the initial presentation and subsequent course of a number of pediatric rheumatic diseases. Although it may also be seen in the context of infection, malignancy, and immunodeficiency, this discussion is limited to rheumatic disease–triggered MAS. Without appropriate treatment MAS has the potential to cause rapid clinical deterioration and death. Because many of the routine laboratory findings associated with this condition are protean and overlap with those of other disorders, particularly sepsis, misdiagnosis through lack of awareness is a significant risk. The reader is referred elsewhere in this issue for more comprehensive information. This section provides an overview of the key features helpful in the recognition of MAS triggered by rheumatic disease and provides a guide to making the diagnosis and its initial management.
Clinical Presentation
Cytopenias in association with fever and splenomegaly are important clues to the possibility of MAS. In the absence of formal diagnostic criteria, those used for the diagnosis of familial HLH have become the default in this condition (See article by Gowdie and Tse elsewhere in this issue for further exploration of this topic). Caution needs to be exercised, however, in the rigid application of these criteria to rheumatic disease-triggered MAS, where significant cell count changes associated with the underlying disease may mask the presence of evolving cytopenias (eg, in Kawasaki disease [KD] and systemic juvenile idiopathic arthritis [sJIA]) or result in misattribution with respect to cause (eg, in systemic lupus erythematosus [SLE]). Under these circumstances falling cell counts, particularly platelets and/or neutrophils, even if still within the normal range, may be an important clue to the presence of MAS. Other suggestive abnormalities of common laboratory parameters are extreme hyperferritinemia, fasting hypertriglyceridemia, or hypofibrinogenemia with coagulopathy and elevation of hepatic enzymes. In rheumatic disease–triggered MAS, clinical or laboratory findings of the underlying rheumatic disorder are also present. These must be carefully sought in all cases of suspected MAS. The most common rheumatologic disorders associated with MAS are SLE, sJIA, and KD. The important clinical and laboratory features that must be looked for when evaluating a patient for the presence of these disorders are outlined in Table 1 . Formal diagnostic criteria for these conditions are dealt with elsewhere in this issue. It should be noted that SLE itself may cause fever and cytopenias; however, the profound neutropenia typically seen in MAS is uncommon and its presence should alert the clinician to the possibility of the latter.
| Kawasaki Disease | Systemic Juvenile Idiopathic Arthritis | Systemic Lupus Erythematosus | |
|---|---|---|---|
| M:F | M = F | M = F | M<F |
| Typical age | Less than 5 yr | No age peak, may occur at any age, uncommon <1 yr | Older children, adolescents |
| Rash | Polymorphous | Evanescent, salmon pink, macules | Photosensitive, esp. malar distribution. Discoid |
| Oromucosal changes | Strawberry tongue Cracked lips | — | Oral ulceration, esp hard palate |
| Conjunctivitis | Nonpurulent | — | — |
| Lymphadenopathy | Cervical >1.5 cm | Generalized, may be associated hepatosplenomegaly | Generalized, may be associated hepatosplenomegaly |
| Arthritis | Present in ∼25% Mostly large joint | Required for diagnosis, may not be present initially | Present in ∼60% Both large and small joint |
| Peripheral changes | Palmar erythema, edema, peeling subacutely | — | Edema if nephrotic, vasculitic skin changes |
| Serositis | Pericarditis | Pericarditis, pleural effusions | Pericarditis, pleural effusions |
| Neurologic | Irritability, aseptic meningitis | — | Chorea, psychosis, headache, seizures |
| Urinalysis | Sterile pyuria | — | Active sediment, Hematuria and/or proteinuria |
| Changes in common laboratory parameters without MAS | Elevation of ESR, CRP, WCC, Thrombocytosis subacutely | Elevation of ESR, CRP, WCC, PLT Ferritin markedly raised Anemia common | Elevation of ESR. CRP usually normal. Hemolytic Anemia, low PLT and WCC may occur |
| Autoantibodies | — | — | Positive ANA, aPL, anti-dsDNA, anti-Sm antibodies |
Approach to Investigation
The investigations that should be ordered when MAS is suspected and the values that suggest its presence, based on the current criteria for HLH, are outlined in Box 1 . The current criteria also include testing natural killer cell activity and levels of soluble CD25; however, these may not be available in all laboratories. Although demonstrating excessive hemophagocytosis in bone marrow or lymph node biopsies provides good evidence of the presence of MAS, its absence does not exclude MAS. Even in fatal cases of HLH the sensitivity of autopsy samples from these tissues for the detection of hemophagocytosis has been reported to be just 39% and 74%, respectively.
Full blood examination (≥2 of three cell lines affected)
Hemoglobin <90 g/L
Neutrophils <1 × 10^9/L
Platelets <100 × 10^9/L
Fasting triglycerides
≥3 mmol/L
Fibrinogen
≤1.5 g/L
Ferritin
≥500 μg/L
Bone marrow or lymph node biopsy:
Excessive hemophagocytosis
Investigations that may be useful in the diagnosis of an underlying rheumatologic disorder are outlined in Table 1 . Because MAS may be triggered by conditions other than rheumatic diseases, in particular infection and malignancy, appropriate investigations to exclude these possibilities should also be undertaken. In the absence of an identifiable trigger, genetic testing for primary HLH should be performed irrespective of the age of the child. Although primary HLH typically manifests in infancy, presentations in older children and adults are being increasingly recognized.
Treatment Overview
After the diagnosis of MAS is confirmed or, in a critically ill child in whom a complete evaluation is not possible, considered highly likely, treatment should be commenced without delay. In situations where infection cannot be excluded, concurrent treatment with appropriate antimicrobial therapy should be given. In general, the initial treatment of MAS is the same irrespective of the underlying trigger. High-dose intravenous steroid pulsed methylprednisolone (30 mg/kg/dose over 30–60 minutes, maximum 1 g) administered daily is considered first-line therapy. This is typically continued for 3 days or until clinical and laboratory parameters begin to improve. Therapy is usually then switched to daily divided-dose steroids, starting at 2 mg/kg/d. Other treatments that may be used in the acute management of MAS complicating rheumatic diseases include cyclosporin, intravenous immunoglobulin, and anakinra. These agents are most often considered in critically unwell children or those who fail to respond to corticosteroids. On rare occasions, in children whose disease is resistant to the previously mentioned measures, the chemotherapy protocol designed for the treatment of primary HLH involving the administration of dexamethasone and etoposide is required. In general, the therapy needed to control rheumatic disease-triggered MAS will also treat the underlying rheumatic disorder. Additional disease-specific therapy is required only in patients with KD for whom intravenous immunoglobulin remains the only therapy proved to reduce the risk of coronary artery aneurysms. After the episode of MAS is controlled, the long-term management of these patients is determined by their underlying rheumatic disorder.
The febrile child with pancytopenia
Macrophage activation syndrome secondary to:
Systemic lupus erythematosus
Systemic juvenile idiopathic arthritis
Kawasaki disease
The differential diagnosis of fever in association with pancytopenia includes such entities as sepsis, myelodysplastic syndromes, and malignancy, all of which pediatricians are familiar with and routinely work-up, treat, and refer when appropriate. Less commonly appreciated is the rheumatologic differential of macrophage activation syndrome (MAS). This potentially fatal disorder, a secondary form of hemophagoctyic lymphohistiocytosis (HLH), may complicate the initial presentation and subsequent course of a number of pediatric rheumatic diseases. Although it may also be seen in the context of infection, malignancy, and immunodeficiency, this discussion is limited to rheumatic disease–triggered MAS. Without appropriate treatment MAS has the potential to cause rapid clinical deterioration and death. Because many of the routine laboratory findings associated with this condition are protean and overlap with those of other disorders, particularly sepsis, misdiagnosis through lack of awareness is a significant risk. The reader is referred elsewhere in this issue for more comprehensive information. This section provides an overview of the key features helpful in the recognition of MAS triggered by rheumatic disease and provides a guide to making the diagnosis and its initial management.
Clinical Presentation
Cytopenias in association with fever and splenomegaly are important clues to the possibility of MAS. In the absence of formal diagnostic criteria, those used for the diagnosis of familial HLH have become the default in this condition (See article by Gowdie and Tse elsewhere in this issue for further exploration of this topic). Caution needs to be exercised, however, in the rigid application of these criteria to rheumatic disease-triggered MAS, where significant cell count changes associated with the underlying disease may mask the presence of evolving cytopenias (eg, in Kawasaki disease [KD] and systemic juvenile idiopathic arthritis [sJIA]) or result in misattribution with respect to cause (eg, in systemic lupus erythematosus [SLE]). Under these circumstances falling cell counts, particularly platelets and/or neutrophils, even if still within the normal range, may be an important clue to the presence of MAS. Other suggestive abnormalities of common laboratory parameters are extreme hyperferritinemia, fasting hypertriglyceridemia, or hypofibrinogenemia with coagulopathy and elevation of hepatic enzymes. In rheumatic disease–triggered MAS, clinical or laboratory findings of the underlying rheumatic disorder are also present. These must be carefully sought in all cases of suspected MAS. The most common rheumatologic disorders associated with MAS are SLE, sJIA, and KD. The important clinical and laboratory features that must be looked for when evaluating a patient for the presence of these disorders are outlined in Table 1 . Formal diagnostic criteria for these conditions are dealt with elsewhere in this issue. It should be noted that SLE itself may cause fever and cytopenias; however, the profound neutropenia typically seen in MAS is uncommon and its presence should alert the clinician to the possibility of the latter.
