Tropical Infection Induced Hemophagocytic Lympho -

HLH is a rare and potentially fatal syndrome of pathologic immune dysregulation characterized by clinical signs and symptoms of extreme inflammation. Based upon the cause, HLH may be primary (familial or associated with immune deficiency syndromes) mainly occurring in pediatric age or secondary to infection, malignancy, or autoimmune condition .[1,2] The diagnosis of this condition is based upon the ‘clinical and laboratory criteria’ developed by HLH study Group of the Histiocyte Society 2004; having 5 out of 8 of the following: (1) fever, (2) splenomegaly, (3) peripheral cytopenias (affecting at least 2 of 3 cell lineages), (4) hypertriglyceridemia (>265 mg/dL) and/ or hypofibrinogenemia (<1.5 g/dL), (5) hemophagocytosis in bone marrow, spleen, lymph nodes, or liver (6) serum ferritin >500 mg/L, (7) low or absent natural killer cell activity, (8) increased soluble CD25 concentration (a chain of soluble IL-2 receptor) >2400 U/ml.[3]


Introduction
HLH is a rare and potentially fatal syndrome of pathologic immune dysregulation characterized by clinical signs and symptoms of extreme inflammation.Based upon the cause, HLH may be primary (familial or associated with immune deficiency syndromes) mainly occurring in pediatric age or secondary to infection, malignancy, or autoimmune condition . [1,2]The diagnosis of this condition is based upon the 'clinical and laboratory criteria' developed by HLH study Group of the Histiocyte Society 2004; having 5 out of 8 of the following: (1) fever, (2) splenomegaly, (3) peripheral cytopenias (affecting at least 2 of 3 cell lineages), (4) hypertriglyceridemia (>265 mg/dL) and/ or hypofibrinogenemia (<1.5 g/dL), (5) hemophagocytosis in bone marrow, spleen, lymph nodes, or liver (6) serum ferritin >500 mg/L, (7) low or absent natural killer cell activity, (8) increased soluble CD25 concentration (a chain of soluble IL-2 receptor) >2400 U/ml. [3]fection induced HLH has been seen most frequently with viral (most commonly Ebstein-Barr virus) and numerous bacterial and parasitic infections. [4,5][8][9] We report 3 cases of tropical fever presenting to the emergency department complicated by HLH.
The clinico-pathological features, laboratory data, treatment and outcome of the all 3 cases (2 scrub typhus and 1 dengue) are presented in (Table 1).
Dengue (NS1 Ag, IgM and IgG antibody), Widal, Visceral Leismaniasis (RK 39 antibody), hepatitis B surface antigen, antihepatitis C virus antibody, HIV ELISA gave negative results.Blood and urine cultures were sterile.A diagnosis of scrub typhus with multi-organ dysfunction was established.However patient did not improve, and his clinical and laboratory parameters further worsened.He had continuous high grade fever with increasing ventilator requirement.PaO2/FiO2 ratio decreased to 88 with increased lung infiltrates on repeat CXR, Hb dropped to 7.4, TLC increased to 14.2 x 10 9 /l and thrombocytopenia persisted (57 x 10 9 /l).Initially a possibility of ventilator associated pneumonia was kept and ceftriaxone was changed to imipenem after sending cultures for endotracheal aspirate, blood and urine.Despite this, patient did not improve.All cultures were sterile and serum procalcitonin was normal (0.1 ng/ml).A possibility of secondary was kept in view of persisting high grade fever, cytopenias and hepatosplenomegaly.Serum ferritin was 1823 mg/l, serum triglyceride was 763 mg/dl and bone marrow examination showed hemophagocytosis.Patient was started on dexamethasone on September 24.A dramatic improvement was observed, fever subsided and patient was extubated on September 27.Hb, TLC and platelet counts improved (10.4 g/ dl, 10.4 x 10 9 /l and 207 x 10 9 /l respectively); serum creatinine normalised (0.5 mg/dl); and AST, ALT and ALP decreased (56, 78 and 209 respectively); serum creatinine normalised (1.0 mg/dl); and AST, ALT and ALP decreased (51, 64 and 257 respectively).Patient had made a complete recovery on a follow up visit at the medicine outpatient department 15 days after the discharge.

Case 2
A 40 years old man presented on October 25, 2015 with high grade fever for 10 days and rapidly progressive dyspnea for 7 days.On physical examination, GCS was E4V5M6, BP of 100/60, PR of 100/min, RR of 26/min, temperature 39 °C and oxygen saturation (SpO2) was 76% on room air.He had pallor but no cyanosis, clubbing, pedal edema, jugular venous distension, lymphadenopathy, skin rashes or eschar.Respiratory system examination revealed bilateral diffuse crackles.Per abdomen, liver was palpable 3 cm below costal margin and spleen was just palpable on deep inspiration.Central nervous system and A diagnosis of scrub typhus with HLH and multi-system involvement was made.Initially patient was managed with antibiotics alone.However during hospital stay, he developed altered mental status, which was managed with a short course (3 days) of dexamethasone.Investigation showed a Hb improved (10.9 g/dl, 7.4 x 10 9 /l and 232 x 10 9 /l respectively); serum creatinine normalised (1.0 mg/dl); and AST, ALT and ALP decreased (51, 64 and 257 respectively).
Patient had made a complete recovery on a follow up visit at the medicine outpatient department 10 days after the discharge.

Case 3
A 25 years old man presented on November 19, 2015 with high grade fever for 7 days, rapidly progressive dyspnea for 2 days and altered sensorium for 1 day.On physical examination, patient was agitated with GCS of E3V4M5, BP of 127/70, PR of 128/min, RR of 32/min, temperature 38.8 °C and SpO2 was 96% on oxygen supplementation with Fio2 0.5 and flow 12 l/min.He had no pallor, cyanosis, clubbing, pedal edema, jugular venous distension, lymphadenopathy, skin rashes or eschar.Respiratory system examination revealed bilateral diffuse crackles, predominantly on basal regions.Per abdomen, liver was palpable 2 cm below costal margin and spleen was not palpable.Central nervous system examination did not show signs of meningeal irritation or any focal neurological deficit and cardiovascular examination was unremarkable.Investigation showed a Hb of 12.9 g/dl; TLC of 18.2 x 10 9 /l; platelet counts of 54 x 10 9 /l; creatinine level of 1.4 mg/dl; total bilirubin of 3.0 mg/dl; AST, ALT and ALP of 3314 IU/l, 1779 IU/l and 245 IU/l respectively; LDH of 4849 IU/L; INR of 1.12; and fibrinogen of 3.88 g/l.ABG revealed PaO2/FiO2 ratio of 106 and a CXR showed bilateral lung infiltrates mainly involving lower zones.Liver was 18.5 cm and spleen was 11.9 cm in size on ultrasonography.
Patient was intubated and put on mechanical ventilation with ARDS protocol.He was started on ceftriaxone and doxycycllin.
An IgM serology for Dengue was positive.Rapid kit test and peripheral smear for Malaria, serological tests for Leptospirosis (IgM antibody), Scrub Typhus (IgM antibody), Widal, Viral Hepatitis (hepatitis A virus IgM, hepatitis E virus IgM, hepatitis B surface antigen, anti-hepatitis C virus antibody), HIV ELISA gave negative results.Blood and urine cultures were sterile.A diagnosis of severe Dengue with multi-organ involvement was made.However patient did not respond, and he had continuous high grade fever with persisting altered sensorium and ventilatory requirement.
Hb dropped to 8.4.A possibility of secondary HLH was kept in view of persisting fever and development of bicytopenia.Serum ferritin was 17190 mg/l, serum triglyceride was 304 mg/ dl and bone marrow examination showed hemophagocytosis.Patient was started on dexamethasone followed by improvement of clinical and laboratory parameters.Patient had made a complete recovery on a follow up visit at the medicine outpatient department 7 days after the discharge.

Discussion
Tropical fevers are defined as infections that are prevalent in, or unique to tropical and subtropical regions of the world.Some of these occur throughout the year and some especially in rainy and post-rainy season.These fevers mainly include infectious diseases like Leptospirosis, Enteric fever, Malaria, Dengue and Scrub typhus (can be remembered as mnemonic LEMDS).Most of these tropical infections have overlapping clinical features, multi-system involvement often requiring intensive care unit care and advance life support measures like vasopressor support, mechanical ventilation, hemostatic resuscitation and renal replacement therapy and have an increased morbidity and mortility. [10]fections are a major trigger for adult HLH, an appropriate targeted antimicrobial therapy is a cornerstone of management.Patients who are clinically stable and respond to treatment of the underlying infection may be able to avoid HLH-specific treatment.However, for severely ill patients, initiation of HLHspecific therapy should not be delayed while awaiting resolution of an underlying infection.In general, treatment entails the suppression of an overactive immune system.
The current treatment protocol of adult or acquired HLH is based on the pediatric HLH-94/-2004 protocol. [1,2]Not all patients with acquired HLH need to be started on the full protocol.Immunosuppressive agents (including corticosteroids, intravenous immunoglobulin, rituximab, cyclosporine alone or in combination) are mainstay of treatment for most of the acquired HLH and infection triggered HLH responds well with corticosteroid alone.However if the disease worsens or does not respond rapidly, full therapy must be initiated quickly. [11,12]H is a life threatening condition and is often missed in adults.It is diagnosed with an immediate need for treatment due to imminent respiratory, hepatic, renal, or hematopoietic failure, without a definitive diagnosis as to whether HLH has a hereditary background (degranulation assay and/or mutation analysis reports pending).Control of overt inflammation is of utmost importance . [2]

Table 1 :
Clinico-pathological characteristics, laboratory data, treatment and outcome of 3 adult patients with tropical infection induced HLH (2 scrub typhus and 1 dengue) Investigation showed an Hb of 9.9 g/dl; TLC of 7 x 10 9 /l; platelet counts of 66 x 10 9 /l; creatinine level of 1.6 mg/dl; total bilirubin of 4.3 mg/dl, AST, ALT and ALP of 631 IU/l, 131 IU/l and 312 IU/l respectively; LDH of 5115 IU/L; INR of 1.0; and fibrinogen of 2.3 g/l.ABG revealed PaO2/Fi02 ratio of 105 and a CXR showed diffuse bilateral lung infiltrates.Liver was 18 cm and spleen was 13 cm in size on ultrasonography.