Haemophagocytic lymphohistiocytosis (HLH) secondary to miliary tuberculosis

indian journal of tuberculosis xxx (xxxx) xxx

Available online at www.sciencedirect.com

ScienceDirect journal homepage: http://www.journals.elsevier.com/ indian-journal-of-tuberculosis/

Case report

Haemophagocytic lymphohistiocytosis (HLH) secondary to miliary tuberculosis Ashish Ranjan a, Ramesh S. Pal b,*, Amit Kumar c, Umesh Chandra Ojha b a

National Institute of TB & Respiratory Diseases New Delhi 110030 India Deptt. of Pulmonary Medicine, ESI Postgraduate Institute of Medical Science and Research, New Delhi India c Deptt. of Pulmonary Medicine, VMMC & Safdurjung Hospital, New Delhi India b

article info

abstract

Article history:

HLH is a rare, life-threatening, hematologic disorder resulting from prolonged and exces-

Received 23 July 2019

sive activation of antigen presenting cells (macrophages, histiocytes) and CD8+ T cells. It is

Accepted 10 August 2019

characterized by fever, pancytopenia,splenomegaly and haemophagocytosis in bone

Available online xxx

marrow,liver or lymph node. This hyperinflammatory condition is often triggered by a variety of agents or events, mostly genetic or infectious. HLH secondary to TB, have 100 %

Keywords:

mortality in absence of anti-tubercular treatment .Since it mimics other disorders, its

Haemophagocytic

timely diagnosis remains a challenge. We report a case of hemophagocytic syndrome

lymphohistiocytosis

associated with disseminated tuberculosis in an immunocompetent man managed with

Tuberculosis

anti-tubercular treatment and corticosteroid as immune modulator.

Life threatening

1.

© 2019 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.

Introduction

Haemophagocytic lymphohistiocytosis (HLH) is a rare clinical entity which is potentially fatal, characterised by ineffective exaggerated immune response and pathologically represents dysregulation of the activation and proliferation of macrophages leading to uncontrolled phagocytosis of blood cells and haematopoietic precursors throughout the reticuloendothelial system including the bone marrow with Infiltration of activated histiocytes and lymphocytes in various organs.1e3 HLH is classified into primary (Genetic) and secondary (Infection, malignancy or autoimmune).4 Mycobacterium tuberculosis is an important pathogen a “great mimicker” with diverse range of presentation. More than 50 cases of HLH

secondary to TB are reported worldwide & have 100% mortality in the absence of Antitubercular treatment.5 Here we report a case of HLH secondary to miliary tuberculosis in a north Indian middle aged immunocompetent man.

2.

Case presentation

A 40 year male admitted with presenting complaint of fever with chills, intermittent in character, moderate in grade for 3 months associated with intermittent cough with minimal expectoration, weight loss and loss of appetite. He is chronic alcoholic and non-smoker. There is no previous h/o

* Corresponding author. Deptt. of Pulmonary Medicine, ESI Postgraduate Institute of Medical Science and Research, New Delhi India. E-mail addresses: [email protected] (A. Ranjan), [email protected] (R.S. Pal), [email protected] (A. Kumar), [email protected] (U. Chandra Ojha). https://doi.org/10.1016/j.ijtb.2019.08.006 0019-5707/© 2019 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved. Please cite this article as: Ranjan A et al., Haemophagocytic lymphohistiocytosis (HLH) secondary to miliary tuberculosis, Indian Journal of Tuberculosis, https://doi.org/10.1016/j.ijtb.2019.08.006

2

indian journal of tuberculosis xxx (xxxx) xxx

hemoptysis, altered bowel habit, urinary symptoms, joint pain, history of jaundice, tuberculosis and drug intake in past. On general examination he was conscious oriented, but chachexic and pale. No icterus present, no Clubbing, and JVP was not raised. There was a rash on left lower limb anteriorly above the ankle. He was Hypoxic, hypotensive and tachypneic at the time of admission (spo2 -76% at room air, PR-90/Min,BP90/60 mm Hg,RR-28/min). His Chest examination revealed diminished movements of left side with raised vocal fremitus, vocal resonance, bronchial breathing and fine crypts at lower axillary & posterior region. Abdominal examination showed soft non tender hepatosplenomegaly. Cardiovascular examination was essentially normal. Initial investigations showed Microcytic Hypochromic Anaemia (Hb-8.8 gm) pancytopenia (TLC-3200/cmm, Platelet count-62000/cmm), Hypoalbuminemia, (S.Albumin
2.2gm/dl), deranged liver function tests (serum bilirubin
1.8mg%, Serum Protiens-4.7 gm/dl, SGOT -185IU/L, SGPT- 64IU/L, Alkaline PO4 -975IU/L) and hyponatremia, (serum Na þ
123 mEq/l). Kidney function test and Random blood glucose were normal. Chest X-ray and CT scan chest available at the time of presentation showed left lower zone consolidation (Figs. 1 & 2). Accordingly patient was put on broad spectrum antibiotics, inhaled bronchodilators and oxygen support meanwhile extensive workup was done to reveal the cause of fever and consolidation. Dengue serology, RA factor, typhidot, mantoux test, malaria antigen and sputum for AFB stain were negative, HIV,HbSag,& Anti HCV was non reactive, blood & urine cultures were sterile, sputum for pyogenic culture and fungal stain found to be sterile and negative for any fungal elements respectively. During the course of treatment, patient continued to have fever spikes after one week, he was very weak, bed ridden, irritable, developed seizures two times and became unconscious for short duration. Thorough clinical examination revealed decreased tone, power in both upper and lower limbs with increased reflexes and without any sensory loss. Fundus examination showed choroid tubercles. MRI brain was normal but, MRI spine shows area of altered signal intensity in C6-C7 vertebral bodies, canal stenosis with adjacent myelopathy, likely spondylodiscitis. USG abdomen showed Hepatosplenomegaly with mild ascites and cholelithiasis.

Fig. 1 e Left lower zone consolidation.

Fig. 2 e CT section showing left lower lobe consolidation.

Repeat x -ray chest shows miliary mottling and it was confirmed by CECT thorax (Fig. 3) with random nodules in lung parenchyma more in middle and lower lung fields and associated bilateral pleural effusion. A diagnosis of HLH secondary to disseminated Koch's was suspected. So a battery of tests to ascertain the diagnosis were done notable as deranged prothrombin time e(T) 17.7 (C)13.0 INR1.57, APTT (T)-75.3 (C)
35.5, raised D-Dimer-325ng/ml (Normal-less than 200 ng/ml), Increased FDP-16ug/ml (Normal 0e10),LDH-246.5IU/L. ANA and anti dsDNA were negative, Serum ferritin - 505.4 units. (Normal-less than 400units), Serum triglycerides were raised significantly. A diagnosis of Hemophagocytic lymphohistiocytosis (HLH) was made, As it fulfilled Criteria for HLH (2004 and 2009 protocol). Antitubercular therapy with rifampicin, INH, pyrazinamide and ethambutol was started along with inj. Dexamethasone 8 mg 12hourly.He became afebrile within one week and gradually improved in terms of appetite and neurological symptoms.

Fig. 3 e CT section showing military nodules, consolidation & B/L effusion.

Please cite this article as: Ranjan A et al., Haemophagocytic lymphohistiocytosis (HLH) secondary to miliary tuberculosis, Indian Journal of Tuberculosis, https://doi.org/10.1016/j.ijtb.2019.08.006

3

indian journal of tuberculosis xxx (xxxx) xxx

3.

Fig. 4 e Chest x ray showing resolution of lesions.

Skin lesion subsided gradually. He was discharged after 15 days of starting ATT. Steroid was tapered and stopped after 8 weeks. After 8 months ATT was stopped. He gain weight just more than double. Chest x-ray showed complete resolution (Fig. 4). During follow up after 1 year of discharge he remains asymptomatic.

Discussion

In this case we diagnosed the case of HLH secondary to disseminated Koch's. We suspected disseminated Koch's based on clinical findings and supported by radiological investigation and ophthalmological examination. HLH is a disorder of macrophage lineage characterized by abnormal hemophagocytosis.6 The pathophysiological hypothesis suggests that CD8 cells and activated natural killer cells secrete stimulatory cytokines, which are responsible for the abnormal activation of macrophages causing hyper secretion of pro-inflammatory cytokines including TNF-alpha, interferon gamma and interleukins.7 HLH is classified as primary and secondary, primary being due to genetic factors mainly while secondary causes may be due to various aetiologies’ including malignancies, infections, autoimmune diseases and drugs (see Table 1).5,8 Diagnosis of HLH is made by adopting HLH Diagnostic criteria 2004.9 A new proposed diagnostic criteria 200910 (Table 2) is also came into existence to more cases of HLH as 2004 criteria being more stringent and more of a clinical trial tool. Our case fulfilled 2004 and 2009 criteria to retain the diagnosis of HLH. A scoring system has also been developed and validated to generate a diagnostic score referred to as H Score that estimates the probability of HLH. A score of more than equal to 250 has a probability of 99.9% while score of less than equal to 90 has a probability of less than 1%.In our case H score was 204 with a probability of more than 74%.11 The pathogenesis of HLH in TB is not known clearly but phenomenon seems related to immune dysregulation. TB induces Th-1 response normally. The cytotoxicTh-1 cells and macrophages increase the efficiency of cytotoxic lymphocytes and the capacity of macrophages to proliferate but defective cytotoxic T cells and natural killer cells produce an unregulated and ineffective immune response leading to bacterial proliferation and immunological stimulation and natural

Table 1 e Aetiologies’ of secondary HLH. Infection Virus-herpes virus group, parvovirus B19, myxovirus, parainfluenza virus, HIV, hepatitis, enterovirus, morbillivirus

Bacteria-Brucella, mycobacteria, salmonella, mycoplasma, ehrlichia, rickettsia, borrelia, common bacteria

Immune Disorders Duncan's disease (Purtilo diaksyndrome), Che Higashi syndrome, asplenia, cytotoxic drugs

Inflammatory Diseases Systemic lupus erythematosus, Still's disease, rheumatoid arthritis, scleroderma, sarcoidosis, Kikuchi syndrome, Crohn's disease, histiocytic cytophagic panniculitis

Neoplasms Malignant lymphoma (especially T cell lymphoma, angioimmunoblastic lymphadenopathy)

Drug Phenytoin, carbamazepine, minocycline, phenobarbital

Hodgkin's lymphoma, tricholeukocyte leukaemia, myelodysplastic syndrome, solid neoplasm

Fungal-candida, histoplasma, aspergillus, cryptococcus Parasites-anguillulose babesia, leishmania, plasmodium, toxoplasma

Please cite this article as: Ranjan A et al., Haemophagocytic lymphohistiocytosis (HLH) secondary to miliary tuberculosis, Indian Journal of Tuberculosis, https://doi.org/10.1016/j.ijtb.2019.08.006

4

indian journal of tuberculosis xxx (xxxx) xxx

Table 2 e HLH criteria 2004 & 2009. 2004 HLH Criteria

2009 HLH Criteria

a. Molecular diagnosis consistent with HLH. Pathologic mutations of PRF1, UNC13D or STX11 are identified Or b. Fulfilment of five of eight of the following criteria  Fever  Spleenomegaly  Cytopenias (affecting at least two of three lineages in the peripheral blood)  Hemoglobin <9 g/100 ml (in infants <4 weeks: hemoglobin <10 g/100 ml) Platelets <100  103/ml  Neutrophils <1  103/ml  Hypertriglyceridemia (fasting, 265 mg/100 ml) and/or hypofibrinogenemia (150 mg/100 ml)  Hemophagocytosis in BM, spleen or lymph nodes  Low or absent NK cell activity  Ferritin 500 ng/ml  Soluble CD25 (soluble IL-2 receptor)>2400 U/ml (or per local reference laboratory

a. Molecular diagnosis consistent with HLH or X-linked lymphoproliferative syndrome (XLP). or b. Fulfilment of at least three of four following criteria  Fever  Splenomegaly  Cytopenias (minimum 2 cell lines reduced)  Hepatitis

c. Fulfilment of at least one of four following criteria  Hemophagocytosis  [ Ferritin  [ sIL2Ra (age based)  Absent or very decreased NK function d. Other supportive diagnostic features  Hypertriglyceridemia  Hypofibrinogenemia  Hyponatremia

killer cells may further fail to destroy proliferating immune cells that result into cytokine storm with uncontrolled macrophage proliferation manifesting as a variety of clinical and laboratory abnormality.12 Fever and tissue wasting caused byTNF Alpha,13 cytopenia from heamophagocytosis in the bone marrow and decreased haematopoiesis by inhibitory cytokines like TNF alpha and IL-beta and others. Haemolysis leads to increased bilirubin and increased LDH, hyponatremia is due to syndrome of inappropriate antidiuretic hormone14 and serum ferritin elevation reflects increased interleukin 1 beta. Triglycerides are increased due to lipoprotein lipase inhibition by TNF Alpha, increase in interferon gamma and liver damage leads to hypoalbuminemia, coagulopathy is related to thrombocytopenia, disseminated intravascular coagulation or hypofibrinogenemia possibly. Hypofibrinogenemia may be caused by activated macrophages activating factor X leading to activation of common pathway. HLH is known to have an acute onset and increasing mortality risk up to 52% as the disease progresses.1,2 Shea YF et al in his review reported 53 cases of TB associated with HLH and 52.8% of them survived.15 Cause of death in TB associated HLH seems to be immunological disturbance and disseminated TB.16 Early diagnosis followed by antitubercular treatment and/ or immunomodulator therapy alongwith supportive intensive care is key for survival of a patient of HLH associated TB. Brastianos PK et al reported 65.5% survival rate among 29 patients who received therapy, 12 out of 20 received combination of ATT and immunomodulator therapy while 7 out of 9 received ATT only. No patient survived who was not treated.12

Main immunomodulator used are glucocorticoids. Actually steroids control intense inflammatory reaction and cytokines storm thus improving clinical outcome, however the exact doses of steroids are not reported so far. Other immunomodulators which are used in, are, intravenous immunoglobulin (IVIG), chemotherapy with etoposide vincristine, plasmapheresis, and splenectomy.

4.

Conclusion

HLH with disseminated TB is rare but serious condition and requires high degree of clinical suspicion for its early diagnosis. Treatment should be given at earliest in form of antitubercular therapy and/or immunomodulators if required. Timely intervention is important in preventing unwanted mortality and morbidity.

references

1. Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis. 2007;7:814e822. 2. Verbsky JW, Grossman WJ. Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives. Ann Med. 2006;38:20e31. 3. Janka G. Hemophagocytic lymphohistiocytosis: when the immune system runs amok. Klinische Padiatrie. 2009;221(5):278e285. 4. Janka GE. Hemophagocytic syndromes. Blood Rev. 2007;21(5):245e253.

Please cite this article as: Ranjan A et al., Haemophagocytic lymphohistiocytosis (HLH) secondary to miliary tuberculosis, Indian Journal of Tuberculosis, https://doi.org/10.1016/j.ijtb.2019.08.006

indian journal of tuberculosis xxx (xxxx) xxx

5. Creput C, Galicier L, Buyse S, Azoulay E. Understanding Organ dysfunction in hemophagocytic lymphohistiocytosis. Intensive Care Med. 2008;34:1177e1187. 6. Larroche C. Hemophagocytic lymphohistiocytosis in adults: diagnosis and treatment. Jt Bone Spine. 2012;79(4):356e361.  n P, Lo  pez-Guillermo A, 7. Ramos-Casals M, Brito-Zero Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2013:26. 8. Claessens YE, Pene F, Tulliez M, Cariou A, Chiche JD. Lifethreatening hemophagocytic syndrome related to mycobacterium tuberculosis. Eur J Emerg Med. 2006;13:172e174. 9. Henter JI, Horne A, Arico M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124e131. 10. Filipovich AH. Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematol Am Soc Hematol Educ Prog. 2009. 11. Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive

12.

13.

14.

15.

16.

5

hemophagocytic syndrome. Arthr Rheumatol. September 2014;66(No. 9):2613e2620. Brastianos PK, Swanson JW, Torbenson M, Sperati J, Karakousis PC. Tuberculosis-associated haemophagocytic syndrome. Lancet Infect Dis. 2006;6:447e454. Shin BC, Kim SW, Ha SW, Sohn JW, Lee JM, Kim NS. Hemophagocytic syndrome associated with bilateral adrenal gland tuberculosis. Korean J Intern Med. 2004;19:70e75. Satomi A, Nagai S, Nagai T, et al. Effect of plasma exchange on refractory hemophagocytic syndrome complicated with myelodysplastic syndrome. Ther Apher. 1999;3:317e319. Shea YF, Chan JF, Kwok WC, et al. Haemophagocytic lymphohistiocytosis: an uncommon clinical presentation of tuberculosis. Hong Kong Med J. 2012;18:517e525. Eliopoulos G, Vaiopoulos G, Kittas C, Fessas P. Tuberculosis associated hemophagocytic syndrome complicated with severe bone marrow failure and disseminated intravascular coagulation. Nouv Rev Fr Hematol. 1992;34:273e276.

Please cite this article as: Ranjan A et al., Haemophagocytic lymphohistiocytosis (HLH) secondary to miliary tuberculosis, Indian Journal of Tuberculosis, https://doi.org/10.1016/j.ijtb.2019.08.006