Hemophagocytic lymphohistiocytosis secondary to infections: A tropical experience!

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.

Full text

6/22/2020 Hemophagocytic lymphohistiocytosis secondary to infections: A tropical experience!
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J Postgrad Med. 2015 Apr-Jun; 61(2): 112–115.
doi: 10.4103/0022-3859.150904: 10.4103/0022-3859.150904
PMCID: PMC4943449
PMID: 25766345
Hemophagocytic lymphohistiocytosis secondary to infections: A
tropical experience!
P Kodan, M Chakrapani, M Shetty, R Pavan, and P Bhat
Department of Medicine, Kasturba Medical College, Manipal University, Mangalore, India
Address for correspondence: Dr. Chakrapani M, Email: chakrapani2009@hotmail.com
Received 2014 Apr 26; Revised 2014 Jun 9; Accepted 2014 Nov 6.
Copyright : © 2015 Journal of Postgraduate Medicine
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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.
KEY WORDS: Hemophagocytic lymphohistiocytosis, infection, steroids, unresolving fever
Introduction
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.
Case Series
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

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(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.
Discussion
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]
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, 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]

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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 /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 (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.
2
2

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[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.
Footnotes
Source of Support: Nil
Conflict of Interest: None declared.
References
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. [PMCID: PMC3368378] [PubMed: 22560573]
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.
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. [PubMed:
11595993]
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.

6/22/2020 Hemophagocytic lymphohistiocytosis secondary to infections: A tropical experience!
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943449/?report=printable 5/9
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. [PubMed: 24157300]
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. [PubMed: 24156177]
7. Gerfaud-Valentin M, Jamilloux Y, Iwaz J, Sève P. Adult-onset still's disease. Autoimmune Rev.
2014;13:708–22. [PubMed: 24657513]
8. Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematology Am
Soc Hematol Educ Program. 2009:127–31. [PubMed: 20008190]
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. [PMCID: PMC3285509]
[PubMed: 22089101]
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. [PubMed: 23331391]
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. [PubMed: 18085676]
12. Larroche C. Hemophagocytic lymphohistiocytosis in adults: Diagnosis and treatment. Joint Bone
Spine. 2012;79:356–61. [PubMed: 22464018]
13. Créput C, Galicier L, Buyse S, Azoulay E. Understanding organ dysfunction in hemophagocytic
lymphohistiocytosis. Intensive Care Med. 2008;34:1177–87. [PubMed: 18427781]
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. [PubMed: 225008]
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. [PMCID: PMC7185531] [PubMed:
18045564]
16. Brastianos PK, Swanson JW, Torbenson M, Sperati J, Karakousis PC, kousis PC. PC-associated
haemophagocytic syndrome.cytic syndrome. PC synd. 6:447–54. [PubMed: 16790385]
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. [PubMed: 20870590]
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. [PubMed: 21163825]
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.
[PMCID: PMC3610451] [PubMed: 23559726]
20. Rosado FG, Kim AS. Hemophagocytic lymphohistiocytosis: An update on diagnosis and pathogenesis.
Am J Clin Pathol. 2013;139:713–27. [PubMed: 23690113]
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. [PMCID: PMC3794258] [PubMed:
24027258]

6/22/2020 Hemophagocytic lymphohistiocytosis secondary to infections: A tropical experience!
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943449/?report=printable 6/9
22. Ansuini V, Rigante D, Esposito S. Debate around infection-dependent hemophagocytic syndrome in
paediatrics. BMC Infect Dis. 2013;13:15. [PMCID: PMC3549728] [PubMed: 23324497]
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. [PubMed: 20972297]
24. Ray S, aKundu S, SSaha M, MChakrabarti P. Hemophagocytic syndrome in classic dengue Fever. J
Glob Infect Dis Glo. 3:399–401. [PMCID: PMC3250000] [PubMed: 22224008]
25. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Ann Rev Med. 2012;63:233–
46. [PubMed: 22248322]
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. [PMCID: PMC5779429] [PubMed: 24452132]
27. Tan LH, Lum LC, Omar SF, Kan FK. Hemophagocytosis emophagocyt Comprehensive report of six
cases. J Clin Virol irol. 55:79–82. [PubMed: 22789140]
28. Ohno T, Shirasaka A, Sugiyama T, Furukawa H. Hemophagocytic syndrome induced by Plasmodium
falciparumium falciparumkawa%2. Int J Hematol emat. 64:263–6. [PubMed: 8923789]
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. [PubMed: 14508800]
30. Sehgal SC. Leptospirosis in the horizon. Natl Med J India. 2000;13:228–30. [PubMed: 11190049]
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. [PubMed: 9398130]
Figures and Tables

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Table 1
Characteristics of secondary HLH patients
M – Male; F – Female, Y – Yes; N – No; CSA – Cyclosporine; NA – Not available
Case No. 1 2 3 4 5
Age (yrs) 32 22 41 64 20
Sex F M M F M
Underlying
infection
Dengue Tuberculosis Dengue Tuberculosis Malar
Fever Y Y Y Y Y
Lymphadenopathy N Y Y N N
New onset
organomegaly
Y Y Y N N
Pan/bi-cytopenia Y Y Y Y Y
Triglyceride
(mg/dl)
NA 110 310 390 308
Ferritin (mg/dl) >100000 595 24036 2180 6677
Bone marrow Hemophagocytosis Hemophagocytosis — Hemophagocytosis Hemo
Treatment Steroid+etopside+CSA Steroid Steroid+Etopside Steroid+etopside+CSA Stero
Outcome Recovered Recovered Recovered Recovered Recov

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Table 2
Proposed HLH diagnostic criteria, 2009
Molecular diagnosis of hemophagocytic lymphohistiocytosis
(HLH) or X-linked lymphoproliferative syndrome (XLP).
OR
At least 3 of 4:
Fever
Splenomegaly
Cytopenias (minimum 2 cell lines reduced)
Hepatitis
and
At least 1 of 4:
Hemophagocytosis [Figure 1]
↑Ferritin
↑sIL2R (age based)
Absent or decreased NK function
Other results supportive of HLH diagnosis:
Hypertriglyceridemia
Hypofibrinogenemia
Hyponatremia

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Figure 1
Ravenous macrophage-hemophagocytosis of RBCs by macrophage seen
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