Haemophagocytic syndrome in intensive care: The great pretender

Abstract

The haemophagocytic syndrome is a unique disease process in which the dysregulation of the patient’s immune system leads to an inflammatory storm which rapidly ravages through multiple organ systems, generating life-threatening end-organ dysfunction. Since it usually mimics other conditions frequently encountered in the critical care population – most notably septic shock – its diagnosis is elusive and the condition remains under-recognized and under-reported. We present a concise review of the pathophysiology and clinical features of the heamophagocytic syndrome and discuss the main diagnostic and therapeutic issues relevant to the management of this condition in the critically ill patient. Increasing awareness about the haemophagocytic syndrome amongst intensive care physicians will facilitate earlier recognition and timely management.

Introduction

The haemophagocytic syndrome (HS) is a unique disease process characterized by the dysregulation of the patient’s immune system, which in response to various internal and external stimuli generates a pathological inflammatory storm which rapidly ravages through multiple organ systems, generating life-threatening end-organ dysfunction. HS comprises a spectrum of disorders with a set of common clinical features: prolonged fever, an explosive systemic inflammatory response, rapidly progressive multi-organ failure, haemophagocytosis and abnormal coagulation. ¹

HS can be classified into primary (genetic) and secondary (reactive). Primary HS generally occur in early childhood in the context of one of several hereditary conditions involving mutations in proteins regulating T lymphocyte and NK-cell cytotoxicity. Secondary HS occur in the adult population as an acute acquired condition triggered by and underlying insult, most frequently infectious or autoimmune.

It is not uncommon for the manifestations of HS to be clinically indistinguishable from those of septic shock and on many occasions, this protean condition can mimic other infectious and inflammatory syndromes commonly encountered in the intensive care unit. What is more, the distinction between HS and sepsis is further blurred by the fact that the spark that ignites the inflammatory cascade of HS is usually infectious. In view of all these, it is not surprising that HS has remained and elusive diagnosis.

In the light of recent evidence suggesting that the prevalence of HS in the critically ill population is actually much higher than initially suspected and in view of the very high mortality associated with this condition if not promptly identified and treated, it is important that general intensivists become more familiar with the condition and its general management.

Pathophysiology

Inflammation is a tightly regulated immunological process which requires the participation of several subtypes of leucocytes and the activation of complex soluble mediator cascades. Regulation of the inflammatory process by means of apoptosis, which entails the destruction and removal of immune cells through a series of pre-programmed signalling stages, is necessary for the resolution of inflammation once infection has been cleared and for the initiation of tissue repair. ²

The HS essentially represents a state of derailed inflammation in which apoptosis is profoundly impaired, resulting in unopposed macrophage activation leading to a persistent cytokine storm and widespread organ dysfunction. Whilst in the familial forms of HS several gene mutations involving lymphocyte cytotoxic proteins have been recently identified; the pathogenesis of acquired HS remains obscure. ³ It is likely that a set of variable penetrance mutations affecting cytotoxicity genes involved in the regulation of apoptosis confer certain individual susceptibility to the disease. When this predisposition is coupled with an additional insult acquired throughout adult life, the immune dysregulation of HS results. In the overwhelming majority of cases, the trigger for HS is an infectious insult, most frequently in the form of a viral illness associated with Epstein-Barr virus (EBV) or cytomegalovirus. Other triggers include flares-up of autoimmune disorders, rheumatic diseases – most notably rheumatoid arthritis, haematological malignancies and certain drugs.

Clinical presentation

The immunopathological hallmarks of HS are unopposed monocytic activation and a marked cytokine over-production. These mechanisms generate what is essentially a severe systemic inflammatory response syndrome (SIRS), usually accompanied by marked hyperpyrexia, lymphadenopathy and hepatosplenomegaly. ⁴ In cases associated with haematological malignancy, skin findings are prominent.

Overall, the clinical course of HS is usually explosive and rapidly progressive, with most patients developing evidence of multiple organ failure within 48 h.

The inflammatory surge affects multiple organ systems, producing acute kidney injury, acute lung inflammation potentially evolving into the acute respiratory distress syndrome (ARDS) and acute liver injury with a predominantly hepatitic pattern. Up to 30% of patients can also present with acute neurological dysfunction, in the form of confusion, seizures or encephalopathy. The activation of the clotting cascade and the presence of a pro-thrombotic endothelium signify that most patients will have deranged clotting, with a small proportion presenting with full-blown disseminated intravascular coagulation (DIC).

Haemophagocytosis – the pathological engulfment and destruction of peripheral blood cells by activated macrophages in the reticulo-endothelial system – is a distinguishing feature of HS that can result in any combination of anaemia, thrombocytopenia and neutropenia. Very frequently however, the presence of haemophagocytosis can go unrecognized since cytopenias are seen daily in the ICU as a result of sepsis or side effects of drugs. To further confound matters, post-mortem studies have demonstrated that patients with profound septic shock can normally exhibit some degree of haemophagocytosis.

Diagnosis

Although the diagnostic rules for paediatric HS are well established, in adults there are no prospectively validated diagnostic criteria and the clinician must still rely on a combination of clinical, biochemical and histopathological data. As a rule of thumb, the diagnosis of HS should be considered in any patient with prolonged fever and evidence of multi-organ failure in the absence of microbiological isolates or a clear infectious aetiology.

From the biochemical point of view, patients with HS can display a wide range of abnormalities which are common to the patient with septic shock and multi-organ failure, uraemia and acute elevation in creatinine levels, deranged liver function tests, prolonged clotting times and hypo-fibrinogenaemia, metabolic acidosis and a marked elevation in inflammatory markers. ⁵ Two laboratory features that are relatively specific to HS are hypertriglyceridaemia and the finding of remarkably high levels of serum ferritin. ⁶ An important caveat regarding ferritin is that it behaves as an acute phase protein and thus is non-specifically elevated in many pro-inflammatory states although ferritin levels in the range seen in HS are rarely encountered in other inflammatory disorders. ⁷ Several strategies have been proposed to increase the specificity of ferritin dosing in HS, such as dosing specific isoforms or increasing the threshold value for diagnosis.

The histopathological hallmark of HS is the demonstration of active haemophagocytosis. This is most frequently performed on bone marrow samples but can also be done on lymph node or skin biopsies. Defining the cut-off value for the number of haemophagocytic units necessary to establish the diagnosis on tissue samples and distinguishing between the ‘pathological’ haemophagocytosis of HS and the ‘reactive’ haemophagocytosis of sepsis are still contentious issues. ⁸

Although the diagnostic performance of several serum markers has been investigated, no single assay has demonstrated sufficient sensitivity and specificity to be useful in isolation. Some of the molecules that have been assessed are CD163, which is a marker of monocytic activation and sCD25, which is a soluble receptor for interleukin-2 (IL-2). In the near future, these tests based on flow cytometry may prove to be extremely useful but for the time being they mostly remain limited to reference centres and are not readily available in general hospitals.

Treatment and outcomes

Regarding the clinical management of HS, the identification and treatment of the igniting trigger are as important as treating the immune hyper-activation itself. Usually, the epidemiological background, clinical history and physical findings are sufficient to establish the trigger but occasionally the underlying cause remains hidden and can only be established in retrospect. ⁹

The management of HS triggered by infection represents a difficult clinical challenge: on the one hand, the use of immunosuppressive drugs can temper the inflammatory response and minimize end-organ damage but on the other hand, the administration of these drugs in the context of uncontrolled infection can result in a septic flare-up. This delicate balance between the prospect of benefit and the potential for harm can only be resolved on a patient-to-patient basis and with careful consideration of all clinical issues. Focused diagnostic investigation and microbiological confirmation of infection can assist clinical decisions. However, in situations where patients are extremely unwell, it may be necessary to commence antimicrobial and immunosuppressive therapy simultaneously. ¹⁰

There are no randomized controlled trials informing therapeutic decisions in adult HS, and the choice of immunosuppressive drug used to treat the immune hyper-activation rests upon expert opinion. Most regimes will include pulsed methylprednisolone, which has demonstrated to improve outcomes in paediatric patients. A second drug is added and frequent choices are cyclosporin, methotrexate, cyclophosphamide and intravenous immunoglobulin (IVIG). The chemotherapeutic agent etoposide is used for severe EBV-related HS. ¹¹ In refractory cases, salvage therapies may include biological agents and stem cell transplantation, although in these instances the risks are extremely high.

Even in the best case scenario where HS is promptly recognized and treated, the short-term outcome remains poor. Due to under-recognition and under-reporting biases, it is difficult to establish the precise mortality but most reports suggest a survival-to-discharge of less than 50%.^12–14

Conclusion

In spite of recent progress in the understanding of its pathophysiology and underlying molecular dynamics, HS remains a clinical challenge for the intensivist. The first difficulty is being able to reliably identify the relatively rare cases of HS hidden in the midst of the large population critically ill patients with systemic inflammation. This can only be achieved if a high index of suspicion is maintained and therefore the diagnosis of HS should be considered in any patient presenting with SIRS, an elevated ferritin level and any combination of hepatosplenomegaly, deranged liver function tests and cytopenias. Once the diagnosis is established, starting potent immunosuppressive treatment in a debilitated critically ill patient on multi-organ support who is already prone to infection always poses a dilemma. Patients who survive their first bout of HS are at increased risk of early relapse or late recurrence and therefore require ongoing surveillance and regular follow up.

Increasing awareness about the manifestations of HS and including this complex condition in the differential diagnosis for the acutely unwell patient with SIRS will facilitate earlier recognition and treatment of cases. Clearly, further molecular and clinical research is still needed, and these results will shed light not only on the intricacies of HS but also on the role of macrophage-mediated immunity in sepsis and inflammation in general.