Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. It most frequently affects infants from birth to 18 months of age, but the disease is also observed in children and adults of all ages. HLH can be classified into primary and secondary HLH. The highest incidence in those <3 months. The male-to-female ratio is close to 1:1. In adults, there may be a slight male predisposition.
19 years female, with no comorbids and no known drug allergy, presented to ER from outside hospital with
– H/O fever – low grade, intermittent for initial 3 days following which high grade, intermittent for last 4 days.
– H/O vomiting * 3 days – non bilious. Non projectile, non blood stained.
– H/O shortness of breath * 2 days.
– H/O rashes over both upper limbs * 2 days with bruising over IV cannulation sites.
Menstural history: irregular cycles, LMP= 2 months ago, spotting P/V noted 2 days back.
Airway Patent, self-maintained.
Breathing RR – 26/ min, Spo2 – 99% RA, B/L air entry equall and absent in basal zones bilaterally, no added breath sounds.
Ciculation BP – 140/ 70 mmHg. HR – 138/ min, CVS -Tachycardic, S1S2 normal, no murmur, JVP – Normal, PA – Soft, non-tender, no organomegally, bowel sounds heard.
Disability GCS – E4V5M6 [15/ 15] Moving all 4 limbs CBG – 121mg/dl
Exposure Temp: 103o F Few bruises notes at IV line sites, few petechial rashes over bilateral upper limbs.
VBG pH – 7.32 PCO2 – 37 mmHg PO2 – 16 mmHg BE -7 mmol/ L HCO3 – 19.3 mmol/ L LAC – 1.78 mmol/ L
⦁ Complete blood count suggestive of pancytopenia with marked reticulocyte count and deranged liver function. ⦁ Peripheral smear suggestive of normocytic, normochromic anemia with thrombocytopenia (done outside). In our hospital microcytic, hypochromic anemia with thrombocytopenia. ⦁ CRP: 200, LDH: 1688, Ferritin: 15,306, Procalcitonin: 0.90, Trop-I : 0.002, NTproBNP: 531.TGL: 425 ⦁ Dengue NS-1: Negative, IgM: negative, IgG: positive, MP-QBC: negative, Scrub typhus IgM: negative. ⦁ Salmonella Typhi O & H positive in 1:320 dilution. Salmonella Para Typhi A&B negative in 1:20 dilution ⦁ ANA/ Anti HAV-IgM/ HEV-IgM/ Anti HBc IgM : non-reactive ⦁ EBv Abs to viral capsid Ag (VCA) IgG/ EBV(NA) IgG antibody: negative ⦁ SARS COV2 IgG antibody: positive ⦁ Echo: normal, Ultrasound abdomen: normal, Coombs test (direct) : negative. ⦁ Blood culture: Proteus species growth present, Urine routine pus cells present. ⦁ Suggested bone marrow biopsy (not done).
Hemophagocytosis is the engulfment of hematopoietic cells by activated macrophages acting outside of usual immune system regulations. Hemophagocytic lymphohistiocytosis (HLH) covers a wide array of related diseases including HLH, autosomal recessive familial HLH (FHL), familial erythrophagocytic lymphohistiocytosis, viral-associated hemophagocytic syndrome, and autoimmune-associated macrophage activation syndrome (MAS). These disorders feature severe cytopenias due to this uncontrolled hemophagocytosis. Other laboratory signs and clinical symptoms result from disordered immune regulation and cytokine storm. The term primary HLH refers to an underlying genetic abnormality causing the disorder, whereas secondary HLH indicates that the disorder is secondary to underlying conditions such as infection, autoimmune/rheumatologic, malignant, or metabolic conditions. For the purposes of this review, FHL will indicate cases with a primary genetic cause, secondary HLH will refer to cases secondary to infection, malignancy, or metabolic disorders, and MAS will refer to cases associated with autoimmune diseases. Primary HLH consists of monogenic disorders that mainly affect the perforin-mediated cytotoxicity of cytotoxic T lymphocytes and natural killer cells. Secondary HLH occurs as a complication in various settings such as infection, malignancy, autoimmune disease, and post-allogeneic hematopoietic stem cell transplantation. Both primary and secondary HLH are characterized by uncontrolled hypercytokinemia that results in myelosuppression and vascular endothelium damage.
It is estimated that approximately 1 child in 3000 admitted to a tertiary care pediatric hospital will have HLH, which corresponds to several cases per centre per year. Earlier reviews reported much lower rates of incidence, likely reflecting under diagnosis of the condition. As an example, in a series from the 1970s that reported an incidence of 1.2 children per million per year, the diagnosis of HLH was made antemortem in only 11 of 32 patients.
HLH carries a high acute mortality of around 40% for all groups combined. Malignancy associated HLH has a particularly poor prognosis with acute mortality exceeding 80% and 5-year survival of less than 15%. In ICU patients, the published hospital mortality rates range from 52%7 to 68%. The presence of shock or severe thrombocytopenia indicate increased risk. The maximum serum ferritin elevation concentration is directly correlated with an increased mortality risk, while a rapid fall in serum ferritin levels in response to treatment is associated with a more favourable short-term outcome.
There is large overlap between the definitions for HLH and sepsis. Both conditions share similarities in their pathophysiology, cytokine profile and clinical features. It has to be noted that sepsis may demonstrate a variety of immunological phenotypes, from a predominant inflammatory response to suppressed immune function or a combination of both, and this may be subject to evolution over time. Macrophage activation-like syndrome (MALS) was defined by a modified HScore, HPB and DIC or a combination of these, and was associated with a significant rise in early mortality. This further supports the existence of HLH secondary to bacterial infection, although its true prevalence remains imprecise.
Differentiating HLH from sepsis may be difficult. HLH may be present in the absence of infection but cause an identical clinical presentation to septic shock (sepsis mimic). In addition, HLH can be triggered by infection or predispose to sepsis by virtue of its inherent immune dysfunction. Both conditions can co-exist in the context of an underlying disease such as malignancy or an autoimmune condition. HLH should, be suspected in all critically ill patients with unexplained fever, cytopenias and organ dysfunction, particularly those not responding to aggressive sepsis treatment.
Initial presentation – HLH usually presents as an acute or subacute febrile illness associated with multiple organ involvement. Initial signs and symptoms of HLH can mimic common infections, fever of unknown origin, hepatitis, or encephalitis. With few exceptions, the clinical features are similar regardless of whether an underlying genetic defect has been identified. Some patients have chronic stuttering presentations, with recurrent fevers of unknown origin and manifest only a subset of the classic diagnostic criteria.
The official diagnosis of HLH, established by the Histiocyte Society, is based on fulfilling one or both of the following criteria: 1. A molecular diagnosis consistent with HLH 2. Five out of the following nine diagnostic criteria for HLH: fever, splenomegaly, cytopenias (affecting two or more of three lineages in the peripheral blood), hypertriglyceridemia, hypofibrinogenemia, elevated ferritin, hemophagocytosis in bone marrow/spleen/lymph nodes, low or absent natural killer (NK)-cell activity, or elevated soluble CD25 (interleukin [IL]-2 receptor).
1. History Including travel/drug/sexual/family history etc. 2. Examination Lymphadenopathy, hepato-splenomegaly, rashes, bleeding, signs of organ dysfuction. 3. Initial laboratory tests Full blood count including differential / blood film Routine renal biochemistry and electrolyes Serum ferritin, triglycerides and C-reactive protein. 4. Liver function tests, including AST, ALT, GTT, total bilirubin and LDH. 5. Coagulation screen, including PT, aPTT, fibrinogen, D-dimer ECG, Echocardiogram. 6. Routine imaging CXR Ultrasound scan: abdomen or as clinically indicated CT neck, chest, abdomen, pelvis. 7. Infectious diseases work-up Infectious disease +/- tropical disease consult Cultures from blood, sputum, urine, CSF and other body fluids as clinically indicated. 8. Respiratory virus screen (combined nose/throat swab), HIV screen, hepatitis virology screen EBV, CMV serology and other herpesvirus PCR may be appropriate in paediatric or immunocompromised. 9. Parvovirus B19 serology, Parasitology (blood film for malaria, serology for toxoplasma and leishmaniasis) 10. Fungal screen cultures (BD glucan, PCP from deep respiratory samples). 11. Consider tuberculosis (histopathology, TB cultures +/- TB Gen Xpert of appropriate tissues/fluids as clinically indicated; immunological tests do not have sufficient validity in this setting). 12. Additional tests in immunosuppression Malignancy work-up Haematology consult Bone marrow aspirate / trephine (haemophagocytosis? Leishmania amastigotes?), may need repeat sampling. 13. Auto-immune work-up Rheumatology consult Auto-immune screen. 14. Immunological profiling Other / miscellaneous Cerebrospinal fluid analysis (abnormal in 50%) 15. MRI brain PET scan (infection, malignancy) Tissue sampling (lymphnodes, spleen biopsy etc.) 16. Genetic testing (no acute role; as advised by HLH expert)
⦁ Cytopenias — Cytopenias, especially anemia and thrombocytopenia, are seen in >80 percent of patients on presentation. Platelet counts range from 3000 to 292,000 and hemoglobin levels of 3.0 to 13.6 are typical.
⦁ Serum ferritin levels — A very high serum ferritin level is common in HLH and, especially in children, has high sensitivity and specificity. In the HLH-94 study, ferritin levels greater than 500, 5000, and 10,000 ng/mL were seen in 93, 42, and 25 percent, respectively. Serum ferritin in this range is seen in very few other inflammatory disorders in children, and when it does occur in other syndromes, it is often in the setting of iron overload syndromes (eg, in multiply transfused patients). In adults and neonates, other potential causes of extremely high ferritin levels should also be evaluated. As an example, ferritin levels over 10,000 ng/mL can be seen in neonatal hemochromatosis or fulminant liver failure. While a very high ferritin level is helpful in suggesting the possibility of HLH, a low ferritin (eg, ferritin <500 ng/mL) does not exclude the possibility of HLH. A relatively normal ferritin can occasionally be seen in HLH genetic syndromes. Macrophages are a primary source of ferritin, which may account for the association between HLH and very high ferritin levels.
⦁ Liver function and coagulation abnormalities — Nearly all patients with HLH will have hepatitis, manifested by elevated liver function tests (LFTs), including liver enzymes (AST, ALT, GGT), lactate dehydrogenase (LDH), and bilirubin. Increased triglycerides and abnormal coagulation parameters (especially elevated D-dimer) caused by hepatic dysfunction and disseminated intravascular coagulopathy are also frequently seen. The degree of abnormality ranges from mild to hepatic failure. Liver enzyme levels greater than three times the upper limit have been reported in 50 to 90 percent of patients with HLH , LDH is elevated in 85 percent. Bilirubin levels between 3 and 25 mg/dL are seen in greater than 80 percent. The GGT level is an especially sensitive number to follow because of biliary tract infiltration by lymphocytes and macrophages.
⦁ Hypertriglyceridemia can be due to severe liver involvement, but may not be elevated until the liver has been affected for some time. In a review of patients with HLH associated with a variety of triggers, 68 percent had elevated triglycerides at diagnosis or during the course of the disease]. Coagulation abnormalities due to impaired hepatic synthetic function and/or disseminated intravascular coagulation are common.
⦁ Neurologic findings — Neurologic abnormalities have been observed in one-third of patients with HLH, are highly variable, and may include seizures, mental status changes (including severe changes consistent with encephalitis), and ataxia. Patients with HLH are at risk of developing posterior reversible encephalopathy syndrome (PRES), which presents with headache, altered consciousness, visual disturbances, and/or seizures. On examination, patients may have retinal hemorrhages and optic nerve edema. PRES is associated with characteristic findings on brain magnetic resonance imaging (MRI), including vasogenic cerebral edema predominantly in the posterior cerebral hemispheres.
⦁ MRI of the brain in patients with HLH also may show hypodense or necrotic areas. Approximately 50 percent of patients have abnormalities of the cerebrospinal fluid, which may carry an increased risk for mortality and neurologic sequelae.
For primary HLH, the first step in treatment is generally to suppress the overactive immune system. This is often done using a combination of steroids and chemotherapy, with the goal of putting the disease into remission. After initial treatment, patient will usually undergo an allogeneic stem cell transplant, which replaces their defective immune system with a healthy one from a donor. Donor cells may come from a sibling, a parent or an unrelated donor. A stem cell transplant offers patients the best chance for a cure.
For secondary HLH, the aim is to identify and treat the underlying cause of HLH (such as an infection or cancer). In many cases, by treating the underlying cause, HLH will go into remission. In some cases, however, it will be necessary to use steroids and/or chemotherapy to treat the condition – similar to treatment for primary HLH. Treatment for secondary HLH is determined more by the severity of the disorder and its symptoms, rather than its classification. The biggest hurdle in HLH treatment is identifying alternatives for children who don’t respond to currently available combinations of chemotherapy, steroids and stem cell transplantation.
HLH is a diverse condition with many causes and is likely under-recognized, which contributes to its high morbidity and mortality. HLH is not a disease in itself but rather a clinical syndrome of extreme hyperinflammation, which is triggered by infection, auto-immunity or malignancy, amongst others. Early recognition is crucial for any reasonable attempt at curative therapy to be made. A number of recent studies have contributed to the understanding of HLH pathophysiology, leading to alternate treatment options; however, much work remains to raise awareness and improve the effectiveness of treatment regimens. It should be suspected and actively investigated in any unwell patient with unexplained fever, cytopenias, progressive organ dysfunction and failure to respond to intensive infection management. Treatment revolves around high-quality supportive care, early anti-inflammatory and immunosuppressive therapy and identification and treatment of any precipitating pathology. In a patient with undifferentiated rapidly progressing organ failure, or if the presumed sepsis diagnosis doesn’t quite “feel” right or respond appropriately – think, could this be HLH?
For guiding me with the article, I would like to thank, Dr.Aslesha (Clinical lead – Emergency Department)
“The author declares no conflict of interest”
Dr.Silvera Samson Raj MRCEM Resident, Kauvery Hospital, Chennai.
Comment:*
Nickname*
E-mail*
Website
Save my name, email, and website in this browser for the next time I comment.
