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ORIGINAL ARTICLE
Year : 2023 | Volume
: 22
| Issue : 4 | Page : 532-536
Hemophagocytic lymphohistiocytosis: A scourge for the physician and bane to the bone marrow
Gokul Krishnan, Siddharth Gosavi, Meher Gujral, Nuzha Basheer, Bharath Kumar, Priyanshu Jain
Department of Internal Medicine, Kasturba Medical College, Manipal, Karnataka, India
Correspondence Address:
Siddharth Gosavi
Department of Internal Medicine, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aam.aam_11_23
Abstract
Background: Hemophagocytic lymphohistiocytosis (HLH) is a condition characterized by hyperinflammation. It can occur due to primary genetic defect or secondary to other etiology such as infection and rheumatological conditions. Clinical features include fever, cytopenia, organomegaly and several laboratory abnormalities. It can be a life-threatening condition secondary to worsening cytopenia and multiorgan dysfunction. Aims and Objectives: To study the clinical profile of HLH in a tertiary care hospital in Southern India. Materials and Methods: Our study has reviewed nine cases of HLH among adult patients presented over 5 years (2017-2022). Results: The majority of our cases were secondary to infection and had a hospital stay over two weeks and with a good response to steroid and immunomodulators. Conclusion: We would like to stress upon the importance of awareness of such a condition so that there can be early suspicion and workup including bone marrow examination, enabling early initiating of specific therapy for this fatal condition.
Abstract in French Résumé
Contexte: L'hémophagocytose lymphohistiocytaire (HLH) est une affection caractérisée par une hyperinflammation. Elle peut survenir en raison d'un défaut génétique primaire ou être secondaire à d'autres étiologies telles que l'infection et les affections rhumatologiques. Les caractéristiques cliniques comprennent de la fièvre, une cytopenie, une organomégalie et plusieurs anomalies de laboratoire. Il s'agit d'une affection potentiellement mortelle en raison de l'aggravation de la cytopenie et du dysfonctionnement multi-organes. Objectifs: Étudier le profil clinique de l'HLH dans un hôpital de soins tertiaires du sud de l'Inde. Matériel et méthodes: Notre étude a examiné neuf cas d'HLH chez des patients adultes sur une période de 5 ans (2017-2022). Résultats: La majorité de nos cas étaient secondaires à une infection et ont nécessité une hospitalisation de plus de deux semaines, avec une bonne réponse aux stéroïdes et aux immunomodulateurs. Conclusion: Nous tenons à souligner l'importance de la sensibilisation à cette affection afin qu'il puisse y avoir une suspicion précoce et des examens approfondis, y compris une ponction de moelle osseuse, permettant ainsi de démarrer rapidement une thérapie spécifique pour cette affection mortelle.
Mots-clés: Score H, hémophagocytose lymphohistiocytaire, immunosuppression, hémophagocytose lymphohistiocytaire secondaire
Keywords: H score, hemphagocytic lymphohistiocytosis, immunosuppression, secondary hemophagocytic lymphohistiocytosis
Introduction 
Hemophagocytic lymphohistiocytosis (HLH) is a life- threatening hematological disease which occurs in both adults and the pediatric population. Activated lymphocytes and macrophages rapidly proliferate and release inflammatory cytokines leading to hyperinflammation and cytokine storm syndrome. Severe infection normally leads to HLH. According to the North American Consortium for Histiocytosis, HLH is divided into three definitions:
HLH syndrome – A pathologic immune activation that is commonly associated with genetic lymphocyte cytotoxicityHLH disease – Here distinct immune activation is the issue with both genetic and environmental causesHLH disease mimic.[1]The phenomenon of hyperinflammation observed in HLH is brought about due to dysregulated activation of lymphocytes and macrophages. Under normal conditions, the activation of such cells is kept under strict downregulation. However, this check mechanism is found to be affected in HLH, leading to an increase in the populations of CD8 + T-cells and macrophages, which in turn release various cytokines and chemokines to further propagate the inflammatory process. It has conversely been observed that patients who exhibit a high CD8 + count and hence a low CD4+/CD8 + ratio show lower mortality rates, whereas an elevated CD3 count was observed to be associated with a poor prognosis.[2],[3]
Elimination of activated macrophages occurs through perforin-dependent cytotoxicity, creation of an immunologic synapse and a pore in the macrophage membrane, and delivery of cytolytic granules into the macrophage to initiate cell death and apoptosis. This mechanism fails in HLH. Toll-like receptor activation of the immune system is another cause.
Hemophagocytosis occurs when macrophages surround host blood cells. The presence of red blood cells, platelets, or white blood cells within the cytoplasm of macrophages is a strong diagnostic indicator for HLH. Cytokine storm in HLH consists of interferon gamma, chemokine C-X-C motif chemokine 9, tumor necrosis factor alpha, interleukin-6, interleukin-10, interleukin-12, interleukin-16, interleukin-18, and CD25. Interleukin-18 in particular has been implicated to be very high in macrophage activation syndrome which differentiates it from HLH.[4],[5],[6],[7]
Common triggers for HLH include Epstein–Barr Virus, Kawasaki disease, nivolumab, ipilimumab, chronic granulomatous disease, malignancies, rheumatologic disorders, and HIV. Some of the common genetic mutations are PRF1, UNC13D, STX11, STXBP2, RHOG, and CDC42. The clinical features of HLH are fever, organomegaly, and cytopenia.
Materials and Methods Adult cases of hemophagocytic lymphohistiocytosis that presented to our tertiary care center in Southern India during the period 2017–2022 were considered for the study. The study was initiated after obtaining clearance from the institutional ethics committee Reference number-210/2022).
Results Case 1
A 22-year-old male who is a case of nephrotic syndrome on prednisolone presented with complaints of fever and shortness of breath for a week. He was tested positive for COVID-19 and was started on the treatment for the same. However, there was worsening hypotension, hypoxia, and sensorium. Mechanical ventilation was provided for hypoxia and parenteral antibiotics were initiated suspecting sepsis. He soon developed ventilator-associated pneumonia with Acinetobacter. Endotracheal aspirate also stained positive for acid-fast bacilli. Antibiotics were changed according to sensitivity report of Acinetobacter, and antituberculosis therapy was started for pulmonary tuberculosis. No significant improvement was noted, and there was worsening pancytopenia. Bone marrow examination done for the evaluation of persisting pancytopenia revealed hemophagocytosis. H score was 208. However, he expired secondary to worsening hypotension and multiorgan dysfunction.
Case 2
A 23-year-old male presented with fever for 10 days and bleeding manifestations in the form of epistaxis, hematemesis, and hematochezia. Initial evaluation showed bicytopenia (anemia + thrombocytopenia). The tropical illness workup sent came positive for dengue serology and scrub typhus. He was started on appropriate therapy, but thrombocytopenia was persisting. Bone marrow aspirate performed for thrombocytopenia evaluation showed hemophagocytosis with H-score of 243 (>99% probability of HLH). However, thrombocytopenia improved over the next few days without any HLH-specific therapy.
Case 3
A 27-year-old female presented with fever and jaundice for a week. Bicytopenia (anemia + thrombocytopenia) was seen on laboratory evaluation. Tropical illness workup came positive for scrub typhus. She was started on antibiotic therapy, but no significant improvement was seen clinically as well as in lab parameters. Bone marrow aspirate revealed hemophagocytosis. Further, the HLH evaluation showed an H- score of 247 (>99% probability of HLH). HLH-specific therapy with dexamethasone was initiated. Improvement was noted in patient's condition and was discharged.
Case 4
A 28-year-old female presented with fever, dyspnea, abdominal distension, and swelling of lower limbs for 5 days. Hypotension and hypoxia were present. Investigations revealed pancytopenia, hepatitis, elevated inflammatory markers, and hepatosplenomegaly. Tropical illness workup including blood culture and COVID-19 reverse transcription-polymerase chain reaction was done came negative. She was started on empirical antibiotics suspecting sepsis with septic shock. Supportive management was provided in the form of inotrope and ventilatory support. Further investigations were performed as a part of the evaluation of pyrexia of unknown origin which showed elevated Epstein–Barr virus (EBV), viral load, and urine culture grew multidrug-resistant Klebsiella. Her clinical status continued to worsen with progressive shock, hypoxia, multiorgan dysfunction, new onset gastrointestinal bleed, and persisting pancytopenia. Bone marrow examination showed extensive hemophagocytosis with H-score of 235. It was planned to initiate steroids for HLH, but the patient bystanders were not willing to continue further care and got the patient discharged against medical advice.
Case 5
A 35-year-old female presented fever, pain abdomen, and burning micturition for 15 days. Dengue immunoglobulin M had come positive, and there was bicytopenia and inflammatory markers were elevated. Bone marrow examination performed for the evaluation of persisting cytopenia showed hemophagocytosis with trilineage dyspoiesis, and H-score was 239. It was decided to initiate her on steroid therapy, but the patient was not willing for the same and got discharged against medical advice.
Case 6
A 35-year-old nil premorbid female presented with high-grade fever and migratory polyarthritis for a week. On examination, there was cervical lymphadenopathy. Blood cultures were sterile. Workup done for pyrexia of unknown origin showed generalized lymphadenopathy on positron emission tomography scan, reactive lymph nodes on lymph node biopsy, and hemophagocytosis on bone marrow. H-score was 200. It was suspected to be a case of adult onset still disease-induced secondary hemophagocytosis. She was started on parenteral steroid therapy with methylprednisolone. However, she developed acute onset severe hypoxia due to diffuse alveolar hemorrhage. Intravenous immunoglobulin and tocilizumab were administered after consultation with rheumatologist. Improvement was noted clinically as well as in laboratory markers.
Case 7
A 53-year-old male presented with fever, vesicles over the left forehead affecting the eye and generalized erythematous rash and petechiae. There was hypotension with elevated inflammatory markers. Parenteral antibiotic and inotropic support was provided for suspected septic shock. Blood culture was sterile. Bone marrow aspirate showed hemophagocytosis and H score was193. Antibiotics were continued. Clinical improvement was noted with antibiotics and supportive care without any HLH-specific therapy. Patient was discharged in a stable state.
Case 8
A 58-year-old male presented with fever spikes over the last 5 days. On examination, splenomegaly was noted. Laboratory evaluation revealed pancytopenia with elevated inflammatory markers. Tropical illness workup including blood culture was negative. Hemophagocytosis was seen on bone marrow study and H score was 253. He improved without any HLH-specific therapy and was discharged in stable condition.
Case 9
A 62-year-old male presented with fever and altered mental status for 3 days. He had multiple comorbidities such as diabetes mellitus, systemic hypertension, and a prior history of cerebrovascular accident. On evaluation, he was found to have pancytopenia and lobar pneumonia with septic shock. Blood culture grew Escherichia coli. He was started on parenteral antibiotic therapy as per culture and sensitivity; however, there was no improvement noted. Bone marrow examination revealed hemophagocytosis. He was started on steroid therapy. Clinical improvement and increase in cell counts were noted. On tapering steroids, there was again a worsening of patient's status as a result of which steroid doses were hiked up. Patient recovered with the above treatment and was discharged in stable state after a prolonged hospital stay of over a month.
The following table summarizes the clinical and laboratory of HLH cases presented to our center [Table 1].
Molecular methods were not utilized for any of the cases due to logistic limitations. Five patients met at least 5 out of 8 points according to HLH 2004 diagnostic criteria. H score ranged from 102 to 247 corresponding to probability from 1% to 99%.
Majority of cases were secondary to infective etiology (8/9) and the noninfective cause of HLH seen in one case was adult-onset still disease. The most common infection implicated was dengue (2 cases) followed by one case each of enteric fever, scrub typhus, EBV, Varicella Zoster virus, and COVID-19. There were three focal infections (sinusitis, meningitis, and encephalitis) and no organism could be isolated in each of them.
Total duration of hospital stay among those who survived was more than 14 days in most of the cases with only three cases who were discharged within 2 weeks of admission. Two patients required ICU admission.
Most of the cases were treated with steroid (Methylprednisolone, Dexamethasone). Two of the cases received intravenous immunoglobulin while tocilizumab was given for the case of Adult-onset still disease. This was in addition to the management of underlying causes in form of antibiotics and other supportive care.
Out of nine cases, one patient had expired. This was a 23-year-old male with underlying nephrotic syndrome on steroids who presented with COVID-19 who had worsening hypoxia and shock.
Discussion Hemophagocytic lymphohistiocytosis (HLH) is a condition characterized by excessive immune system activation. It can happen sporadically due to underlying genetic defects or secondary to other triggers like infection.[8]
Diagnostic criteria have been developed for facilitating the diagnosis of HLH which has a very heterogenous presentation and underlying triggers. HLH 2004 was the initial diagnostic criteria formulated during one of the first trials conducted on HLH. However, it is to be noted that the trial included pediatric cases and not adults.
Revised diagnostic criteria were created in 2004 with input from the histiocyte society. The diagnostic criteria were modified by the addition of three criteria: (1) low or absent NK cell activity, (2) hyperferritinemia, and high levels of IL2r. This is in addition to the existing five points of criteria (fever, splenomegaly, cytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis. Modified HLH 2009 criteria were introduced that included hepatitis among other modifications[8],[9][Table 2] and [Table 3].
Table 3: Hemophagocytic lymphohistiocytosis 2009 modified diagnostic criteriaIt is to be noted that not all patients may meet diagnostic criteria at a given point of time during the course of illness, especially during the initial stages. Therefore, it is important to have a clinical suspicion of HLH and further investigations or repeat investigations like repeat bone marrow examination or samples from a different site like lymph node or spleen.
Genetic testing may not be feasible in all cases as not available at all facilities in a developing country like ours, however, we can recommend a genetic testing consult/referral if primary/familial HLH is suspected. Familial/primary HLH can be considered in the case of the following:
Positive family historyRecurrenceExtremely severeNo clear trigger after even after extensive evaluation.In addition to the points mentioned in diagnostic criteria, there are few other supportive evidence too like spinal fluid pleocytosis and/or elevated spinal fluid protein.
At the same time, the initiation of treatment is not to be delayed while waiting to satisfy diagnostic criteria. H score is a scoring system developed to find the probability of person having HLH. It takes into consideration several of the points of the revised HLH diagnostic criteria of 2004 and two extra points: underlying immunosuppression and liver enzyme (aspartate transaminase [AST]).[10]
Regarding the management of HLH, one has to consider the severity and underlying cause. Ideal treatment protocol is dual therapy with etoposide and dexamethasone in addition to management of the underlying cause. However, this regimen is not strictly followed and steroid monotherapy is used.[11] If the underlying cause is of infective etiology as in majority of our cases, then extra caution to be taken of the risk of worsening of infection after immunosuppression. We have attained a favorable response in majority of cases.
In case of doubt, if HLH-specific therapy is to be initiated, then few points can guide us.
serum ferritin increasing from 3000 to 10,000 μg/L, D-dimer increasing from 1500 to 4000 ng/mL, and alanine aminotransferase (ALT) increasing from 100 to 500 international units/L over 2 daysFor a patient with fever, hepatomegaly, hemoglobin 10 g/dL, platelets 150,000/μL; clinical factors stable, serum ferritin increasing from 3000 to 5000 μg/L, D-dimer stable at 1500 ng/mL, and ALT/AST approximately 100 international units/L, we would observe the patient, gather more data, and not treat unless further deterioration of clinical or laboratory factors occurred.For a patient with suspected or known underlying rheumatologic disease (sJIA, lupus) or inflammatory bowel disease, fever, hepatomegaly, Hgb 12 g/dL, platelets decreasing from 500,000/μL to 200,000/μL, serum ferritin 10,000 μg/L, D-dimer 3000 ng/mL, and ALT/AST approximately 300 international units/L, we would initiate dexamethasone therapy. Such cases may respond to steroids due to the resolution of the rheumatologic or inflammatory trigger and may not require etoposide.[10] Conclusion Triglyceride, ferritin, and fibrinogen levels can be checked in case of suspicion of HLH and then to decide on bone marrow study to confirm the diagnosisMolecular assays are not a must to meet diagnostic criteriaNot to wait for meeting all points of diagnostic criteria for starting steroids.Acknowledgment
We would like to thank the Manipal Academy of Higher Education for helping us conduct this study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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