Viral infections associated with haemophagocytic syndrome

Haemophagocytic syndrome (HPS) or haemophagocytic lymphohistiocytosis (HLH) is a rare disease caused by a dysfunction of cytotoxic T cells and NK cells. This T cell/NK cell dysregulation causes an aberrant cytokine release, resulting in proliferation/activation of histiocytes with subsequent haemophagocytosis. Histiocytic infiltration of the reticuloendothelial system results in hepatomegaly, splenomegaly, lymphadenopathy and pancytopenia ultimately leading to multiple organ dysfunctions. Common clinical features include high fevers despite broad spectrum antimicrobials, maculopapular rash, neurological symptoms, coagulopathy and abnormal liver function tests. Haemophagocytic syndrome can be either primary, i.e. due to an underlying genetic defect or secondary, associated with malignancies, autoimmune diseases (also called macrophage activation syndrome) or infections. Infectious triggers are most commonly due to viral infections mainly of the herpes group, with EBV being the most common cause. HPS can be fatal if untreated. Early recognition of the clinical presentation and laboratory abnormalities associated with HPS and prompt initiation of treatment can be life saving. HPS triggered by viral infections generally does not respond to specific antiviral therapy but may be treated with immunosuppressive/immunomodulatory agents and, in refractory cases, with bone marrow transplantation. Copyright © 2010 John Wiley & Sons, Ltd.     

Fatal haemophagocytic syndrome and hepatitis associated with visceral leishmaniasis

Haemophagocytic syndrome (HPS) secondary to infections occurs due to excessive, non-malignant proliferation of histiocytes, with resultant haemophagocytosis. The syndrome is essentially treatable, provided timely etiological diagnosis is achieved. In this report, we present a rare case of a child who hailed from Uttaranchal and presented with severe hepatitis. Bone marrow examination revealed an unexpected diagnosis of HPS secondary to visceral leishmaniasis. Despite initiating appropriate antileishmanial treatment, the child had a fatal outcome.     

Paraneoplastic syndrome in haemophagocytic histiocytic sarcoma in a dog

A case of metastatic splenic haemophagocytic histiocytic sarcoma (HHS) in a 6-year-old neutered male flat-coated retriever is described. The main clinical findings were hypoalbuminaemia and regenerative anaemia. The diagnosis was based on histological features and expression of CD11d by the neoplastic cells. Tumour cells were shown to produce interleukin (IL)-6, to phagocytose erythrocytes and to take up albumin, as demonstrated by immunohistochemistry and ultrastructural examination. Quantitative polymerase chain reaction identified increased IL-6 gene expression in affected organs. These findings suggest that neoplastic cells are responsible for the clinical features of HHS, by removing erythrocytes and albumin from the blood and releasing cytokines, such as IL-6.     

Influenza A and the virus associated haemophagocytic syndrome: cluster of three cases in children with acute leukaemia.

At the height of the United Kingdom influenza A epidemic in December 1989, three children receiving treatment for non-T cell acute leukaemia developed pancytopenia with concomitant influenza A infection. Bone marrow histology showed prominent marrow erythrophagocytosis by morphologically mature histiocytes, consistent with the picture of virus associated haemophagocytic syndrome (VAHS). In two cases there was an initial spontaneous recovery, though recurrence of VAHS developed in one case in association with a different viral infection (cytomegalovirus) following autologous bone marrow transplantation. The third child died from cardiorespiratory failure secondary to infection with influenza A and Klebsiella pneumoniae sepsis. It is suggested that influenza A should be added to the list of infective causative agents.     

Tuberculosis and acquired immunodeficiency syndrome

India has the largest HIV-infected population in the world with over 4 million infected. The current evidence indicates that the doubling time of the epidemic in India is less than 2 years. Those infected with Mycobacterium tuberculosis add to the gravity of the situation enhancing both morbidity and mortality in these dually infected patients. With the incomprehensive diagnostic facilities available, it is wise to exploit the situation with utilization of tuberculin test with a different cut off criterion for the early diagnosis of mycobacterial infection amongst HIV positive population, especially when there are financial constraints and lack of diagnostic facilities to get CD4 cell count.     

Large B cell lymphoma presenting initially in bone marrow, liver and spleen: an aggressive entity associated frequently with haemophagocytic syndrome

Yeh Y‐M, Chang K‐C, Chen Y‐P, Kao L‐Y, Tsai H‐P, Ho C‐L, Wang J‐R, Jones D & Chen T‐Y
(2010) Histopathology 57, 785–795 Large B cell lymphoma presenting initially in bone marrow, liver and spleen: an aggressive entity associated frequently with haemophagocytic syndrome Aims: To describe diffuse large B cell lymphoma (DLBCL) presenting initially in bone marrow, liver and spleen (BLS‐type) without lymphadenopathy. Methods and results: The clinicopathological and cytogenetic features of 11 such cases (eight men, three women; mean age: 62.7 years are described). Usually presenting with fever and haemophagocytic syndrome suggesting infection and complicating timely diagnosis, bone marrow examination showed patchy and interstitial infiltration of large tumour cells without sinusoidal involvement. All cases had a high Ki‐67 index (≥90%), commonly a non‐germinal centre/activated B cell immunophenotype and were negative for Epstein–Barr virus and human herpesvirus 6 and 8. The more frequent cytogenetic changes involved chromosomal loci 14q32 and 9p24, as well as del(3)(q21), add(7)(p22), t(3;6), del(8)(p22), +18 and add(19)(p13). Clinical behaviour was very aggressive, with a 2‐year survival rate of 18% (45% of patients died within 3 weeks). High‐dose chemotherapy with haematopoietic stem cell transplantation prolonged survival in one patient. Conclusions: Although it shares with intravascular LBCL a subtle presentation and an aggressive clinical course, this primary BLS large cell lymphoma variant is distinguished by lacking an intravascular component and having different cytogenetic findings.     

Tuberculosis associated immune reconstitution inflammatory syndrome in patients infected with HIV: meningitis a potentially life threatening manifestation

Background

Tuberculosis (TB) is the most common co infection in HIV-infected persons in India, requiring concomitant administration of anti TB and antiretroviral therapies. Paradoxical worsening of tuberculosis after anti-retroviral therapy (ART) initiation is frequently seen.

Objective

To study the frequency, clinical presentation and outcome of paradoxical tuberculosis associated immune reconstitution inflammatory syndrome (TB-IRIS) in HIV infected patients in a TB hospital in North India.

Design

A retrospective chart review of HIV-infected TB patients on anti-tubercular treatment (ATT) at time of ART initiation over a 3?year period. Medical records were reviewed for clinical manifestations and outcome in patients who developed TB-IRIS.

Results

514 HIV-infected patients were enrolled between January 2006 and December 2008. Thirteen (12.6%) of 103 patients who had received ART and ATT simultaneously developed paradoxical TB-IRIS. Clinical presentations of paradoxical TB-IRIS included new lymphadenopathy (n?=?3), increase in size of existing lymphadenopathy (n?=?3), worsening of existing pulmonary lesions (n?=?2), appearance of new pleural effusion (n?=?1) and prolonged high grade fever (n?=?2). Four patients developed new tubercular meningitis as manifestation of TB-IRIS. Our cases developed TB-IRIS a median of 15?days after starting ART (IQR 15?C36). TB-IRIS patients were older (> 35?years) than those with no IRIS (P?=?0.03), but were not distinguishable by CD4 T-cell count, duration of ATT before ART or the outcome of TB treatment. Eight (62%) patients had a complete recovery while 5 (38%) patients with TB-IRIS died, of which majority (n?=?3) had meningitis.

Conclusions

Paradoxical TB-IRIS is a frequent problem during concomitant ATT and ART in HIV-TB co infected patients in north India. Meningitis is a potentially life threatening manifestation of TB-IRIS.     

Fatal mucormycosis and aspergillosis coinfection associated with haemophagocytic lymphohistiocytosis: A case report and literature review

Invasive mould infections are life-threatening and mainly occur in immunocompromised patients. Whereas aspergillosis is described during haemophagocytic lymphohistiocytosis (HLH), only a few cases of concomitant mucormycosis with HLH have been reported. Here, we present an uncommon coinfection of mucormycosis and aspergillosis associated with HLH probably due to a varicella zoster virus (VZV) viraemia which was unresponsive to triple antifungal therapy (liposomal amphotericin B combined with isavuconazole and caspofungin). A review of the cases of mucormycosis with HLH showed that this uncommon association was always lethal and underscored the relevance of screening for mould infections in patients with HLH.     

High levels of IL-10 and determination of other cytokines and chemokines in HIV-associated haemophagocytic syndrome

Haemophagocytic syndrome (HPS) and HIV infection are both associated with cytokine network dysregulation. We therefore analysed plasma levels and mRNA synthesis in peripheral blood mononuclear cells (PBMC) of cytokines, chemokines and chemokine receptors in one HIV-infected patient with HPS. We compared the results with those for eight HIV-infected patients with similar CD4+ T cell counts (207/mm3 versus controls: median 214/mm3) and plasma virus load (4.1 log copies/ml, versus controls: median 4.2 log copies/ml). The HPS patient had a lower viral DNA load in PBMC and higher plasma levels of interferon-gamma, IL-10, and macrophage inflammatory protein (MIP)-1beta. No difference in plasma tumour necrosis factor-alpha (TNF-alpha), IL-6 and MIP-1alpha concentration was observed between the HPS patient and control patients. No difference was observed in TNF-alpha, IL-1beta, IL-10, IL-4, MIP-1alpha, MIP-1beta, RANTES, CXCR-4, and CCR-5 mRNA levels in PBMC, but IL-6 levels were higher in the HPS patient. Our results emphasize the role of IL-10 in the control of immune hyperactivation that is observed in HPS.     

Intravascular lymphomatosis: a case presenting with encephalomyelitis and reactive haemophagocytic syndrome diagnosed by renal biopsy

 

Aims:

To report an unusual instance of intravascular lymphomatosis presented with encephalomyelitis and reactive haemophagocytic syndrome. There was no skin involvement. The diagnosis was made on a renal biopsy. Methods and results : The marrow smear was air dried and stained with Diff-Quik. The tissue sections were stained with haematoxylin and eosin, Masson trichrome, periodic acid–Schiff's reagent, Elastic van Gieson's stain, modified hexamine-silver technique and Martius scarlet blue. Immunohistochemistry for CD45, CD20, CD45RO, Factor VIII related antigen, CD31 and CD34 was performed on paraffin-processed tissue. The marrow smear showed active haemophagocytosis in the histiocytes. The renal biopsy showed intravascular lymphomatosis with tumour cells positive for CD45 and CD20. Conclusion : The possibility of intravascular lymphomatosis should be considered in patients with reactive haemophagocytic syndrome where the underlying cause cannot be found after thorough investigation.     

Fulminant parvovirus B19‐associated pancarditis with haemophagocytic lympho‐histiocytosis in an immunocompetent adult

Myocarditis is a common cardiac disease that is identified on routine postmortem examinations. Initially, coxsackie viruses, other enteroviruses and adenoviruses were thought to be more common causes of myocarditis; however, recently, parvovirus B19 (PVB19) as well as human herpesvirus 6 (HHV6) have entered the arena. We describe autopsy findings of a patient who had a lethal myocarditis with haemophagocytic lympho‐histiocytosis in a course of systemic PVB19 infection. The present case illustrates the unusually severe and rapid course of PVB19 myocarditis with associated haemophagocytic lympho‐histiocytosis leading to death.