Journal of Postgraduate Medicine
 Open access journal indexed with Index Medicus & ISI's SCI  
Users online: 5279  
Home | Subscribe | Feedback | Login 
About Latest Articles Back-Issues Article Submission Resources Sections Etcetera Contact
 
  NAVIGATE Here 
  Search
 
  
 RESOURCE Links
 ::  Similar in PUBMED
 ::  Search Pubmed for
 ::  Search in Google Scholar for
 ::Related articles
 ::  Article in PDF (571 KB)
 ::  Citation Manager
 ::  Access Statistics
 ::  Reader Comments
 ::  Email Alert *
 ::  Add to My List *
* Registration required (free) 

  IN THIS Article
 ::  Abstract
 :: Introduction
 :: Case Series
 :: Discussion
 ::  References
 ::  Article Figures
 ::  Article Tables

 Article Access Statistics
    Viewed6120    
    Printed75    
    Emailed4    
    PDF Downloaded29    
    Comments [Add]    

Recommend this journal


 


 
  Table of Contents     
CASE SERIES
Year : 2015  |  Volume : 61  |  Issue : 2  |  Page : 112-115

Hemophagocytic lymphohistiocytosis secondary to infections: A tropical experience!


Department of Medicine, Kasturba Medical College, Manipal University, Mangalore, India

Date of Submission26-Apr-2014
Date of Decision09-Jun-2014
Date of Acceptance06-Nov-2015
Date of Web Publication13-Mar-2015

Correspondence Address:
M Chakrapani
Department of Medicine, Kasturba Medical College, Manipal University, Mangalore
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0022-3859.150904

Rights and Permissions


 :: Abstract 

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyper inflammatory condition, if not recognized and treated in time. A high index of suspicion can help identify the condition early. This condition can occur in the primary or secondary form. Secondary HLH or hemophagocytic syndrome (HPS) secondary to infections is an important clinical entity especially in tropical world. In this article, we share our experience with this entity and make an attempt to explore literature about ravenous macrophages which occurs secondary to infections. It is a series of six cases of HLH secondary to infectious disease in our center in a coastal city in South India over last one year with follow up.


Keywords: Hemophagocytic lymphohistiocytosis, infection, steroids, unresolving fever


How to cite this article:
Kodan P, Chakrapani M, Shetty M, Pavan R, Bhat P. Hemophagocytic lymphohistiocytosis secondary to infections: A tropical experience!. J Postgrad Med 2015;61:112-5

How to cite this URL:
Kodan P, Chakrapani M, Shetty M, Pavan R, Bhat P. Hemophagocytic lymphohistiocytosis secondary to infections: A tropical experience!. J Postgrad Med [serial online] 2015 [cited 2019 Nov 18];61:112-5. Available from: http://www.jpgmonline.com/text.asp?2015/61/2/112/150904



 :: Introduction Top


Hemophagocytic lymphohistiocytosis (HLH) secondary to infectious disease is an important entity especially in tropics where infectious diseases are rampant and still pose a major threat. A timely diagnosis and prompt treatment can improve the clinical outcome of this otherwise potentially fatal condition! [1],[2],[3]

This article aims to alert the clinicians that in persistent unresolved fever especially in tropics, a diagnosis of secondary HLH should be given due consideration and we present 6 cases in this paper.

[TAG:2]Case Series [/TAG:2]

All patients presented between March 2012 and March 2013 (details shown in [Table 1]) and fulfilled the revised criteria of HLH [4] as listed in [Table 2]. Of them, 5/6 had pathological evidence of hemophagocytosis. The mean age at diagnosis was 33.83 years (range: 20 to 64 years), with a male: female ratio of 2:1. All patients presented with fever. Three patients presented with evidence of hepatomegaly and/or splenomegaly. All of the patients had at least a bi- or trilineage cytopenia, elevated liver enzymes and hyperferritinemia. Two of the cases were secondary to dengue fever and one secondary to disseminated tuberculosis, one secondary to pulmonary tuberculosis, one secondary to malaria (falciparum) and one secondary to leptospirosis. Corticosteroids and etoposide were the most frequently used drugs for treatment. All patients had good recovery and none of them relapsed at a median follow up of 4 months.
Table 1: Characteristics of secondary HLH patients


Click here to view
Table 2: Proposed HLH diagnostic criteria, 2009


Click here to view



 :: Discussion Top


HLH is a hyper-inflammatory condition which may be familial or occur secondary to autoimmune diseases or infection, malignancy or other triggers. [1],[2] Despite advances in the diagnostic work up of febrile patients, HLH remains elusive from the diagnostic capabilities of many clinicians and continues to be a potentially fatal disease entity. [3] The underlying pathophysiology of the disease constitutes an unrestrained immune activation with defective macrophage function regulation. [1] An excessive activation of macrophages leads to a cytokine storm in the host and leads to host tissue damage and organ dysfunction associated with the syndrome. Excessive pro-inflammatory or defective anti-inflammatory responses leading to this cytokine storm can be triggered by host factors or environmental agents. [1][Figure 1]
Figure 1: Ravenous macrophage-hemophagocytosis of RBCs by macrophage seen

Click here to view


The activating or inciting mechanisms differ in patient to patient. Accordingly, a HLH arising in the setting of an underlying genetic mutation is termed familial HLH, in the setting of an underlying rheumatologic disease like rheumatoid arthritis is termed as macrophage activation syndrome (MAS) and in the setting of an underlying infection it is termed as reactive or secondary hemophagocytic syndrome (HPS) or secondary HLH. Case reports describing MAS post bone marrow transplant in patients with juvenile rheumatoid arthritis, or secondary to SLE or dermatomyositis or other autoimmune diseases have been reported. [4],[5],[6] Macrophage and neutrophil activation is a hallmark in conditions like stills disease which can lead to hyperinflammatory condition with HLH. [7],[8] Overproduction of proinflammatory cytokines, uncontrolled activation of T cells, and macrophages associated with decreased natural killer cell and cytotoxic cell functions seem to be the hallmarks of the immunologic abnormalities in MAS. [5] Recent human and murine investigations suggest that all HPSs should be differentiated based on etiology and pathogenesis as treatment strategies for each may vary. [9] However, all etiologies lead to a state of hyper ferritin levels. The precise mechanism of ferritin as a trigger or a bystander in pathogenesis needs to be explored.

The reactive or infection-associated HLH remains a relatively important and yet unfortunately an underdiagnosed entity especially in the tropical world. [10] Various combinations of high grade fever sometimes a second spike of fever after a brief period of recovery which coincides with fresh cytopenias, unresponsiveness to broad-spectrum antibiotics, new onset organomegaly or sudden increase in size of organomegaly in the setting of an infectious disease are some of the diagnostic clues for this disease.In case of infections, a simple blood investigation that shows elevated levels of serum ferritin should raise the suspicion of a coexisting HLH. A tentative diagnosis of HLH for initiation of immunosuppressive therapy can be done when clinical and lab abnormalities exist as defined in revised 2009 HLH protocol. Also, in the resource poor settings, a single value of ferritin more than 10,000 in the absence of iron overload conditions like hemochromatosis and thalassemia syndromes can act as a surrogate marker for HLH with a sensitivity of 90% and specificity of 96%. [11]

HPS secondary to infections has been classified as a separate entity under International classification of diseases by World Health Organization. [10] Viral especially EBV has been linked more commonly with this entity. [11] Other viruses like dengue, herpes, CMV, HIV have been reported to have HPS secondary to them. [10],[11],[12],[13],[14],[15] Secondary HPS has frequently been associated with intracellular pathogens that stimulate Th1 immune response. Of the bacterial infections, the commonly implicated organism is tuberculosis. [16] Other reports with organisms like  Salmonella More Details, leptospirosis, malaria, toxoplasmosis, leishmenia, rickettsia and other organisms have been postulated in secondary HLH. [16],[17],[18] Although case reports and case series have frequently reported the reactive HLH secondary to infectious causes especially in the tropical countries, it continues to remain as an under diagnosed and under-reported entity. [2],[10],[19],[20]

The treatment of secondary HLH includes aggressive treatment of underlying condition along with immunosuppressive therapy. The optimal immunosuppressive therapy is not yet established. Clinicians worldwide use the standard HLH 2004 protocol. [18] However, recent data suggest to a less intense immunosuppressive therapy. As opposed to the familial HLH, where allogenic stem cell transplant is the only curative treatment, most of the infection associated HLH cases respond to a course of corticosteroids. Some patients may need additional treatment with drugs like etoposide and cyclosporine; however, a full course of HLH 2004 protocol is rarely required in them. In our case series, all patients were initiated with dexamethasone at a dose of 10 mg/m 2 /day. Three patients with HLH secondary to underlying tuberculosis, malaria and leptospirosis [Case 2, 5, 6 In [Table 1] each responded to steroid monotherapy. Within 2 days of starting steroids their fever reduced with improvement in cytopenias. However, other three patients needed additional immunosuppressive therapy. One patient with dengue fever had a ferritin values more than 100,000 along with severe pancytopenia. She was given two doses of etoposide iv at a dose of 100 mg/m 2 (reduced dose) at weekly intervals. Other two patients were given one single dose of etoposide following which they became symptomatically better. One patient with dengue and one with tuberculosis however had delayed recovery of platelet count and they were started on oral cyclosporine. CSA was given for duration of three months following which it was tapered and stopped. All the six patients were weaned off the steroids by 6 weeks of initiation. None of the patients required full HLH 2004 protocol treatment. This is in tune with the other case reports and case series of secondary HLH. One possible explanation for this is removal of inciting agent by means of effective antibacterial therapy. Because of its powerful proapoptotic activity, etoposide seems to be very effective in controlling the overactive macrophages in HLH.Pinto et al. describe their unique experience with stem cell transplant in treating secondary HLH in an adolescent. However, results were disappointing. [21] Role of allogenic transplant has not been advocated unlike familial HLH. [18],[21]

Srinivas et al. in their systemic review of Hemophagocytosis syndrome (hps) in tropics found infectious trigger as the cause in 51% of the adult patients. [10] Leishmenia was seen in 40.6%, rickettsia in 18.8% malaria in 15.6% and enteric fever in 9.4%.Viral agents were reported in 30% of hps cases. In children 56% patients were secondary to viruses, 26% secondary to dengue virus, 17.3% were secondary to EBV and 8.7% each to CMV and Parvovirus B 19. [10] Most of the literature on HLH in tropics is centered on few hospitals and includes case reports and case series. Larger studies and trials are required to throw more light on this potentially fatal condition and unfold the mysteries of ravenous macrophages.

In India, HLH associated with dengue fever and malaria with a high parasite index has been documented. [22] In one study from India, the dengue virus has been found to be the most common agent causing HLH in children. [23] Many of the previous case reports of HLH are reported in complicated dengue fever like dengue hemorrhagic syndrome. [24] Crohn's disease and immunosuppression are associated with an increased risk for developing secondary HLH, although none of our patients had underlying disease or immunosuppressed status. [25]

However, cases with classical dengue syndrome have also been reported from Indian subcontinent. [24] In our series also, we report two cases of classical dengue fever with secondary HLH. Our cases add to the existing literature of handful of cases of HLH in dengue. Although more common in tropics a case of elderly female has been described by CDC, USA in which HLH secondary to possible dengue infection proved fatal and physicians in west need to be alerted about possible travel acquired dengue which can have fatal complications like secondary HLH. [26] Tan et al. from Malaysia describe the time-lines of six cases of confirmed dengue with varying severities of hemophagocytosis. [27] Both our patients presented with fever, pancytopenia, organomegaly, high ferritin and fulfilled the criteria of HLH and responded to corticosteroids and etoposide.

HLH secondary to malaria was reported in a young man (case number 5) who had persistent fever, falling counts despite treatment with antimalarials. Ohno et al. had described one of the first cases of hemophagocytosis secondary to malaria (falciparum) which resolved with antimalarials. [28] Park et al. discusses four case reports of HLH secondary to vivax malaria all of which resolved with antimalarials. [29] However, studies in the pediatric population show degree of parasitemia is associated with severity of disease. [22] Similarly our case was secondary to P falciparum malaria with severe parasitemia seen on peripheral smear. The patient responded to corticosteroids. .

HLH secondary to disseminated tuberculosis has been described in past. [10],[16] Pristilla et al. in their review analyzed 36 cases of tuberculosis with secondary HLH. [16] They found fever to be the most common presenting symptom and evidence of extra-pulmonary tuberculosis was found in 83% of cases. In our series, case number 2 a young boy with fever, weight loss, military tuberculosis and choroid tubercles was diagnosed as a case of disseminated tuberculosis. No significant improvement with anti tubercular treatment prompted us to look for other causes and was diagnosed as secondary HLH based on clinical features, high ferritin and bone marrow evidence of hemophagocytosis. Steroids were added to his treatment course and he showed significant improvement within 2 weeks. Similarly an elderly female was diagnosed to have HLH secondary to pulmonary tuberculosis and was started on steroids. However, she did not improve and was further treated with IV etoposide and oral cyclosporine and showed complete remission of symptoms and evidence of hemophagocytosis on follow up after 4 week.Tuberculin test was negative in both our patients. This is consistent with earlier studies which showed negative tuberculin test should never preclude the possibility of overwhelming tubercular infection in HLH.

Leptospirosis is a spirochete which is commonly prevalent in coastal belt of South India. [30] To the best of our knowledge, no case of HLH secondary to this disease in adult has been reported. The diagnostic challenge in making appropriate diagnosis has been discussed in one of the previous case reports from Taiwan in a young male who presented with shock and had evidence of reactive hemophagocytosis. [31] Our patient was a fisherman from the endemic area who presented with fever and oliguria. In due course he developed hepatosplenomegaly, severe cytopenia, ESR of 5, high ferritin and bone marrow evidence of hemophagocytosis. He was treated with corticosteroids and showed complete remission. In leptospirosis possible pathogenesis of HLH due to dysregulated immune system has been described. [16] This complication should be borne in mind by treating physicans. In conclusion with limited experience and lack of guidelines for treatment of tropical HLH, a high index of suspicion is something clinicians should bear in mind.

 
 :: References Top

1.
Canna SW, Behrens EM. Making sense of the cytokine storm: A conceptual framework for understanding, diagnosing, and treating hemophagocytic syndromes. Pediatr Clin North Am 2012;59:329-44.  Back to cited text no. 1
    
2.
Ramos-Casals M, Brito-Zerto P, LP, L-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet 2013. pii: S0140-6736(13)61048-X.  Back to cited text no. 2
    
3.
Sung L, Weitzman SS, Petric M, King SM. The role of infections in primary hemophagocytic lymphohistiocytosis: A case series and review of the literature. Clin Infect Dis 2001;33:1644-8.  Back to cited text no. 3
    
4.
Sreedharan A, Bowyer S, Wallace CA, Robertson MJ, Schmidt K, Woolfrey AE, et al. Macrophage activation.ncbi.nlm.nih.gov/pubmed?term=nelson%2520rp%2520jr%255bauthor%2 Bone Marrow Transplant one ;37:629-34.  Back to cited text no. 4
    
5.
Gorlitsky BR, Zangeneh T, Fuchs D, Cox C. Fifty, febrile, and fatigued: High ferritin as a clue in diagnosis. Am J Med 2013;126:e3-4.  Back to cited text no. 5
    
6.
Thomas A, Appiah J, Langsam J, Parker S, Christian C. Hemophagocytic lymphohistiocytosis associated with dermatomyositis: A case report. Conn Med 2013;77:481-5.  Back to cited text no. 6
    
7.
Gerfaud-Valentin M, Jamilloux Y, Iwaz J, Sève P. Adult-onset still's disease. Autoimmune Rev 2014;13:708-22.  Back to cited text no. 7
    
8.
Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am Soc Hematol Educ Program 2009;127-31.   Back to cited text no. 8
    
9.
Canna SW, Behrens EM. Not all hemophagocytes are created equally: Appreciating the heterogeneity of the hemophagocytic syndromes. Curr Opin Rheumatol heum;24:113-8.  Back to cited text no. 9
    
10.
Rajagopala S,SSingh N. Diagnosing and treating hemophagocytic lymphohistiocytosis in the tropics: Systematic review from the Indian subcontinent. Acta Med Acad cad ;41:161-74.  Back to cited text no. 10
    
11.
Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2008;50:1227-35.  Back to cited text no. 11
    
12.
Larroche C. Hemophagocytic lymphohistiocytosis in adults: Diagnosis and treatment. Joint Bone Spine 2012;79:356-61.  Back to cited text no. 12
    
13.
Cr.62; C, Galicier L, Buyse S, Azoulay E. Understanding organ dysfunction in hemophagocytic lymphohistiocytosis. Intensive Care Med 2008;34:1177-87.   Back to cited text no. 13
    
14.
Risdall RJ, McKenna RW, Nesbit ME, Krivit W, Balfour HH Jr, Simmons RL, et al. Virus-associated hemophagocytic syndrome: A benign histiocytic proliferation distinct from malignant histiocytosis.istiocy isti;44:993-1002.   Back to cited text no. 14
    
15.
Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis 2007;7:814-22.  Back to cited text no. 15
    
16.
Brastianos PK, Swanson JW, Torbenson M, Sperati J, Karakousis PC.kousis PC. PC-associated haemophagocytic syndrome.cytic syndrome. PC synd;6:447-54.  Back to cited text no. 16
    
17.
Niller HH. Myelodysplastic syndrome (MDS) as a late stage of subclinical hemophagocytic lymphohistiocytosis (HLH): A putative role for Leptospira infection. A hypothesis. Acta Microbiol Immunol Hung Hung;57:181-9.  Back to cited text no. 17
    
18.
Cascio A, Giordano S, Dones P, Venezia S, Iaria C, Ziino O. Haemophagocytic syndrome and rickettsial diseases. J Med Microbiol 2011;60:537-42.  Back to cited text no. 18
    
19.
Rajagopala S, Singh N, Agarwal R, Gupta D, Das R. Severe hemophagocytic lymphohistiocytosis in adults-experience from an intensive care unit from North India. Indian J Crit Care Med 2012;16:198-203.  Back to cited text no. 19
[PUBMED]  Medknow Journal  
20.
Rosado FG, Kim AS. Hemophagocytic lymphohistiocytosis: An update on diagnosis and pathogenesis. Am J Clin Pathol 2013;139:713-27.  Back to cited text no. 20
    
21.
Pinto MV, Esteves I, Bryceson Y, Ferrão A. Hemophagocytic syndrome with atypical presentation in an adolescent. BMJ Case Rep MJ C;2013. pii: bcr2013200929.  Back to cited text no. 21
    
22.
Ansuini V, Rigante D, Esposito S. Debate around infection-dependent hemophagocytic syndrome in paediatrics. BMC Infect Dis 2013;13:15.  Back to cited text no. 22
    
23.
Ramachandran B, Balasubramanian S, Abhishek N, Ravikumar KG, Ramanan AV. Profile of hemophagocytic lymphohistiocytosis in children in a tertiary care hospital in India. hospitaPediatr edia;48:31-5.  Back to cited text no. 23
    
24.
Ray S,aKundu S,SSaha M,MChakrabarti P. Hemophagocytic syndrome in classic dengue Fever. J Glob Infect Dis Glo;3:399-401.  Back to cited text no. 24
    
25.
Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Ann Rev Med 2012;63:233-46.  Back to cited text no. 25
    
26.
Sharp TM, Gaul L, Muehlenbachs A, Hunsperger E, Bhatnagar J, Lueptow R, et al.; Centers for Disease Control and Prevention (CDC). Fatal hemophagocytic lymphohistiocytosis associated with locally acquired dengue virus infection - New Mexico and Texas, 2012. MMWR Morb Mortal Wkly Rep 2014;63:49-54.  Back to cited text no. 26
    
27.
Tan LH, Lum LC, Omar SF, Kan FK. Hemophagocytosis emophagocyt Comprehensive report of six cases. J Clin Virol irol;55:79-82.  Back to cited text no. 27
    
28.
Ohno T, Shirasaka A, Sugiyama T, Furukawa H. Hemophagocytic syndrome induced by Plasmodium falciparumium falciparumkawa%2Int J Hematol emat;64:263-6.  Back to cited text no. 28
    
29.
Park TS, Oh SH, Choi JC, Kim HH, Chang CL, Son HC, Lee EY. Plasmodium vivax ivaxodium vivax://www.nhemophagocytic syndrome in an immunocompetent serviceman. Am J Hematol emat;74:127-30.  Back to cited text no. 29
    
30.
Sehgal SC. Leptospirosis in the horizon. Natl Med J India 2000;13:228-30.  Back to cited text no. 30
    
31.
Yang CW, Pan MJ, Wu MS, Chen YM, Tsen YT, Lin CL, et al. Leptospirosis: An ignored cause of acute renal failure in Taiwan. Am J Kidney Dis 1997;30:840-5.  Back to cited text no. 31
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
Print this article  Email this article
 
Online since 12th February '04
2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
Published by Wolters Kluwer - Medknow