Current Medical Issues

REVIEW ARTICLE
Year
: 2020  |  Volume : 18  |  Issue : 2  |  Page : 77--82

Low-volume plasma exchange and low-dose steroid to treat secondary hemophagocytic lymphohistiocytosis: A potential treatment for severe COVID-19?


Vijay Alexander1, Uday Zachariah1, Ashish Goel1, Subramani Kandasamy2, Binila Chacko2, John Victor Punitha3, Sukesh Nair4, Vinoi David5, Savit Prabhu6, KA Balasubramanian6, Ian Mackie7, Elwyn Elias8, CE Eapen1,  
1 Department of Hepatology, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
2 Division of Critical Care, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of Medicine - Medicine Unit I, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
4 Department of Transfusion Medicine and Immunohaematology, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
5 Department of Nephrology, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
6 Department of The Wellcome Trust Research Laboratory, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India
7 Department of Research Haematology, University College London, London, United Kingdom
8 Department of Hepatology, Division of Gastrointestinal Sciences, Christian Medical College, Vellore, Tamil Nadu, India; Liver Unit, University Hospitals Birmingham, Birmingham, United Kingdom

Correspondence Address:
Dr. C E Eapen
Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu
India

Abstract

Secondary hemophagocytic lymphohistiocytosis (sHLH) may be responsible for some of the deaths in adult patients with severe COVID-19. We present our experience of low-volume plasma exchange (PLEX) with low-dose steroid in the treatment of adult patients with sHLH and acute liver failure caused by dengue virus and other nonviral triggers and discuss how this may be effective in the management of severe COVID-19. sHLH is poorly understood and without effective treatment. Endothelium of the capillaries of the lungs and kidneys and of liver sinusoids does not express von Willebrand factor (VWF) in health and is where most macrophages are located. Plasma VWF levels are high in sHLH and require clearance by macrophages, which when activated enlarge and likely block the lumen. Current histology studies neither appreciate microcirculatory sludge nor display endothelial–macrophage interactions. We hypothesize that low-volume PLEX and low-dose steroid may reverse sHLH and improve survival in severe COVID-19 patients with acute lung injury.



How to cite this article:
Alexander V, Zachariah U, Goel A, Kandasamy S, Chacko B, Punitha JV, Nair S, David V, Prabhu S, Balasubramanian K A, Mackie I, Elias E, Eapen C E. Low-volume plasma exchange and low-dose steroid to treat secondary hemophagocytic lymphohistiocytosis: A potential treatment for severe COVID-19?.Curr Med Issues 2020;18:77-82


How to cite this URL:
Alexander V, Zachariah U, Goel A, Kandasamy S, Chacko B, Punitha JV, Nair S, David V, Prabhu S, Balasubramanian K A, Mackie I, Elias E, Eapen C E. Low-volume plasma exchange and low-dose steroid to treat secondary hemophagocytic lymphohistiocytosis: A potential treatment for severe COVID-19?. Curr Med Issues [serial online] 2020 [cited 2020 Oct 31 ];18:77-82
Available from: https://www.cmijournal.org/text.asp?2020/18/2/77/282180


Full Text



 Secondary Hemophagocytic Lymphohistiocytosis in Severe Covid-19 patients



Macrophages, cells of the innate immune system, respond rapidly (within 20–30 min) once the host recognizes an invading microbe by phagocytosis. However, uncontrolled macrophage activation//secondary hemophagocytic lymphohistiocytosis (sHLH) commonly triggered by viruses can lead to cytokine storm, multi-organ failure, and death.

Among hospitalized adult COVID-19 patients, serum ferritin (a marker of macrophage activation) and interleukin-6 (a pro-inflammatory cytokine) levels were significantly higher in nonsurvivors and increased with worsening illness.[1] In view of cytokine storm[2] and sHLH, it has been suggested that severe COVID-19 patients be screened for hyperinflammation (increasing ferritin levels, decreasing platelet counts, and HScore [used to diagnose sHLH]) to consider immunosuppressive therapy.[3]

sHLH pathophysiology is poorly understood and better insight into its mechanisms, and treatment may improve survival.

 Our Hypothesis



Low-volume PLEX and low-dose steroid may improve survival in patients with sHLH and acute lung/liver injury by ameliorating macrophage overactivation. We postulate that this treatment may improve survival in severe COVID-19.

 Support for the Hypothesis



We present our experience using a low-volume PLEX and low-dose steroid protocol [Supplementary Material] to treat patients with sHLH and acute liver failure due to dengue virus and other nonviral triggers. Data from a prospectively maintained database of patients with acute liver failure treated by this protocol in our department were retrospectively analyzed for this purpose, after obtaining approval from our institutional review board and ethics committee. We discuss the link between activation of endothelium and of macrophages in sHLH. Endothelium of the capillaries of the lungs and kidneys and of the liver sinusoids does not express von Willebrand factor (VWF) in health and is where most macrophages are located. Plasma VWF levels are high in sHLH and require clearance by macrophages, which when activated enlarge and likely impede microcirculatory perfusion in these organs. The similarities between sHLH and associated organ failure in severe COVID-19 and viral (dengue)/nonviral triggers and its implications are discussed.

 Our Preliminary Experience With Low-Volume Plasma Exchange and Low-Dose Steroid to Treat Dengue-Induced Secondary Hemophagocytic Lymphohistiocytosis and Acute Liver Failure



Of three patients with dengue-induced sHLH, acute liver failure, and multi-organ failure, treated with this protocol, two patients who did not require mechanical ventilation had reduction in sequential organ failure assessment (SOFA)[4] scores and hyperinflammation and survived [Table 1].{Table 1}

 Our Preliminary Experience With Low-Volume Plasma Exchange and Low-Dose Steroid in Nonviral Acute Liver Injury/failure



Alcohol, drugs, and toxins can also trigger macrophage overactivation, and our preliminary experience with this treatment protocol in acute liver injury/failure or acute-on chronic liver failure is promising. Of our first 100 patients, 72 were treated in the high-dependency unit and 28 in the intensive care unit; 51 had acute liver injury/failure and 38 had acute-on chronic liver failure. These 100 patients underwent a median of three (range 2–5) sessions of PLEX, and 1·5 (0·5–2) litres of plasma was exchanged per se ssion with fresh frozen plasma. Etiologies for liver disease included alcohol (24 patients), phosphorus poisoning (18), and idiosyncratic drug-induced liver injury (16).[5] Of 39 patients (acute liver injury/failure: 15, and acute-on chronic liver failure: 24 patients) tested, all had markedly raised serum sCD163 (marker of macrophage activation) levels and this correlated with disease severity and in-hospital mortality.[6]

Of 21 patients with very severe alcoholic hepatitis[7] (median model for end-stage liver disease [MELD] score of 32 [28–42] and median discriminant function score[7] of 91.8 [70.7–159.6]) treated by this protocol, 13 (62%) survived without liver transplantation.[8] Of 13 patients with idiosyncratic drug-induced liver injury who met criteria for liver transplantation treated by this protocol, six patients survived without liver transplantation.[9] Of ten patients with rodenticidal hepatotoxicity who met the listing criteria for liver transplantation (median MELD score 39 [36–40]) treated by this protocol, five patients (50%) survived without liver transplantation.[10]

Improved survival has been reported with low-volume of plasma exchanged in acute-on chronic liver failure patients with milder grade of disease severity.[11]

 The Possible Link between Activation of Endothelium and of Macrophages in Secondary Hemophagocytic Lymphohistiocytosis



The change in terminology from reticuloendothelial system to mononuclear phagocyte system suggests close link between endothelium and macrophages.

Raised levels of the plasma VWF (a platelet adhesive protein released from endothelium), low levels of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), an enzyme which cleaves VWF, and thrombocytopenia are recognized in viral infections such as dengue.[12] VWF-rich platelet plugs may block microcirculation in acute inflammatory syndromes – termed as secondary thrombotic microangiopathies; reduced microcirculatory perfusion of vital organs is recognized as functional organ failure by a clinician at the bedside.

Endothelial cells lining the capillaries in the lungs and renal glomeruli[13] and sinusoids in the liver[14] do not express VWF in health. These “VWF-free” zones are narrow (diameter of the lung capillaries is 6.3 μm[15] and of the liver sinusoids is 9–10 μm[16]). VWF-rich microthrombi were noted at autopsy in children with reduced ADAMTS13 levels, multi-organ failure, and thrombocytopenia.[17] In a prospective multicenter trial, PLEX led to resolution of organ dysfunction and better 28-day survival in children with multi-organ failure and thrombocytopenia.[18]

Animals (foals) dying of sepsis have increased lung inflammation, increased VWF expression in the lung capillaries, as well as increase in pulmonary intravascular macrophages and VWF positivity demonstrated on the macrophage surface.[19] VWF is removed from the circulation by macrophages and hepatocytes.[20],[21] While macrophages are present in all tissues, they are predominantly located in the liver sinusoids (called Kupffer cells) and lung capillaries.[22]

It seems important to keep these narrow low-pressure “VWF-free” traffic zones patent (i.e., avoid VWF-rich platelet microthrombi to form), to allow free flow of traffic (blood flow) through the capillaries of the lungs and kidneys and sinusoids in the liver. These same narrow traffic zones in the liver and lungs provide “parking slots” for macrophages and may contribute to lumen narrowing as macrophages get activated in sHLH.

 High Von Willebrand Factor Levels in Microcirculation: Relevance of Coiled and Stretched-Out Von Willebrand Factor Forms



VWF molecules released from the endothelial cells travel in the blood stream mainly as coiled forms; hence, the binding sites for platelets and ADAMTS13 are less exposed.[23] When VWF tethered to subendothelial collagen (at site of a vessel wall breach) is stretched out by shear stress of flowing blood, it exposes its platelet binding site. VWF also carries factor VIII (a coagulation factor). Thus, damage to the vessel wall localizes platelets and VWF (and factor VIII).

What are the consequences of increased endothelial VWF expression and of increased VWF levels in microcirculation? In health, high molecular weight VWF multimers (5000–10,000 kDa) comprise the main form of VWF in circulation.[23] In viral sHLH, it is likely that large-coiled VWF may sludge capillaries/liver sinusoids. The stretched-out VWF due to increased shear stress in arterioles attracts more platelets, recognized by the clinician as thrombocytopenia. Microthrombi in the areas of infection may be an innate immune response to contain infection and is termed immunothrombosis.[24]

 Plasma Exchange Protocol May Ameliorate Macrophage Activation and Improve Multi-Organ Dysfunction and Survival in Patients With Acute Liver Injury/failure



High-volume PLEX (8–12 litres of plasma exchanged with fresh frozen plasma daily for 3 days) attenuated innate immune activation, ameliorated multi-organ dysfunction, and improved liver transplant-free survival by about 10% in acute liver failure.[25] As this survival benefit is not seen with renal replacement therapy, we postulate that molecules too large (>60 kDa) to be removed by dialysis may be removed by PLEX in these patients. VWF is the largest known protein in the normal human plasma.[23] High molecular weight VWF multimers (up to 10,000 kDa) will not be removed by dialysis. Raised plasma VWF levels accurately predicted in-hospital mortality in 24 patients with acute hepatotoxicity (20 patients had acute liver injury, while three had acute liver, failure)[26] and in 50 patients with acute-on chronic liver failure.[27] Thus, VWF pheresis may explain the survival benefit of PLEX in patients with liver failure.[28] VWF reduction is being explored to treat acute liver failure syndromes.[26],[29],[30] In patients with raised plasma VWF levels, PLEX reduces plasma VWF levels by two mechanisms: by removing VWF in the pheresed plasma and by supplementing ADAMTS13 (a VWF cleaving protease) in the form of replaced fresh frozen plasma.

The three dengue-induced sHLH and acute liver failure patients in our report [Table 1] had raised plasma VWF levels (3.7–5.7-fold above upper limit of normal). As VWF is cleared by macrophages, we postulate that the increased VWF load in circulation may contribute to continued macrophage activation. We hypothesize that PLEX reduces the raised plasma VWF load, which in turn may ameliorate macrophage overactivation in sHLH patients.

 Acute Failure of Liver/lungs May Be Due to a “traffic Jam” in Its Microcirculation

[Figure 1]{Figure 1}

An acute increase in the number and size of macrophages in the endothelial lining as well as arrival of innate immune cells (such as monocytes and neutrophils) and of large-sized proteins such as VWF (for clearance by macrophages) will further narrow the lumen in the narrow, low-pressure “VWF-free zones” in vital organs. What are the possible consequences of acute obstruction to flow in liver sinusoids and lung/renal capillaries? It is interesting to note that a physiological PLEX occurs through fenestrated endothelial cells lining the hepatic sinusoids in health.[31] Acute reduction in microcirculatory perfusion in a vital organ will lead to acute organ dysfunction, and when reduction in perfusion crosses a critical threshold, tissue necrosis and organ failure are likely.

Why is this “traffic jam” not well recognized on histology studies?

Antemortem tissue biopsies do not retain the free-flowing intravascular contents; hence, microcirculatory sludge in any organ is not appreciated in these biopsies. Newer techniques are needed to study this. It is possible that postmortem studies, i.e. after blood flow in circulation has ceased, may appreciate the microcirculatory sludge better. Indeed, postmortem studies in 50 acute liver failure patients demonstrated congestion of capillaries as the most common histopathological finding in lungs (in 50% of patients), in kidneys (in 58%), and in liver (in 40%). This was associated with hepatic necrosis (in 62% of patients) and acute renal tubular necrosis (in 44%).[32]

 Primary Versus Secondary Hemophagocytic Lymphohistiocytosis: Relevance to Covid-19



Macrophage activation is kept in check by natural killer cells and/or cytotoxic T-lymphocytes. The latter cells may either create a hole on the macrophage surface (via perforins) or encourage macrophage death (through granules with potent cytolytic enzymes [such as granulysin] inserted into the macrophage). Absent/reduced natural killer cell/cytotoxic T-cell function leading to uncontrolled macrophage activation is termed primary HLH.[33]

In contrast to primary HLH, in sHLH, the natural killer cells/cytotoxic T-cells may get overactivated, in an attempt to control the macrophage overactivation. A patient who died of COVID-19 had high concentrations of cytotoxic granules in the peripheral blood CD8 T-cells (32% cells were perforin positive, 64% were granulysin positive, and 31% were positive for both).[34] It is possible that this T-cell overactivation reflects the natural killer/cytotoxic T-cells machinery, attempting to control the macrophage overactivation. The collateral damage by this overactive T-cell response may add to the lung injury.

 How Does Treatment of Dengue-Induced Acute Liver Failure Have Relevance to Acute Lung Injury in Severe Covid-19?



Hyperferritinemia in severe dengue [Table 1] and severe COVID-19[1] patients and raised serum sCD 25 levels[35] and HScore >169[36] in dengue patients suggest macrophage activation syndrome/sHLH [Table 1].

Postmortem lung biopsies indicate sHLH in patients with severe acute respiratory syndrome (SARS) due to SARS-associated coronavirus[37] and avian influenza A (H5N1) infection[38] (marked increase in macrophages in alveoli and in interstitium[37] and hemophagocytosis[37],[38]). Fibrin thrombi in the pulmonary vessels were also noted in one patient.[38] Overactivated CD8 T-cells in a severe COVID-19 patient[34] suggest the expected cytotoxic T-cell response to macrophage overactivation in sHLH.

Raised VWF load in the plasma may trigger continued macrophage activation as macrophages work to clear the VWF load. Macrophage activation triggers cytokine storm. “Traffic jam” in the liver sinusoids (in dengue-induced acute liver failure) and in the lung capillaries (in COVID-19 patients) and in other vital organs will lead to reduced perfusion and failure of these organs.

 Some Points to Highlight in Our Treatment Protocol



Outcomes are best, when treatment is implemented at the stage of acute liver injury, rather than acute liver failureWe start low-dose steroid before starting PLEX and continue for 1–4 weeks after. This strategy appears to ameliorate the secondary macrophage activation syndrome/sHLHLow volume of exchanged plasma appears effectiveThe replacement fluid is fresh frozen plasma from healthy donors[25] at 1:1 volume (so that the pheresed plasma does not render the patient immune depleted and more prone to sepsis. In addition, ADAMTS13 in the infused fresh frozen plasma has a VWF lowering effect)We avoid isolated platelet transfusion in patients with thrombocytopenia in the setting of activated endothelium (reflected by raised plasma VWF levels).[39]

 Implications and Unknowns of the Hypothesis



While our report of viral (dengue)-induced sHLH and acute liver failure is limited to three patients [Table 1], it provides a mechanistic explanation why lung and other multi-organ failure occur in COVID-19 patients. Our preliminary experience with dengue-induced sHLH does not prove that low-volume PLEX and low-dose steroid ameliorate macrophage overactivation and improve survival in viral sHLH. However, our experience with more number of patients with acute liver injury/failure due to other causes (who also have sHLH) treated by this protocol is encouraging.

Plasma obtained from healthy unselected donors from the blood bank was used in PLEX treatment of our three dengue patients. We did neither use convalescent plasma from individuals who recovered recently from dengue nor were dengue antibodies tested in the donor plasma.

Unlike dengue which is arthropod borne, SARS-CoV2 which causes COVID-19 is highly contagious. Hence, healthcare workers need to take appropriate personal protective measures when managing critically ill COVID-19 patients.

Due to concern that steroid may delay viral clearance, it has been suggested that steroid should not be routinely used in patients with COVID-19 and acute lung injury.[40] The risks and benefits of low-dose steroid advocated in our treatment protocol need to be tested in clinical trials of severe COVID-19 patients.

 How to Test the Hypothesis



Markers of activation of macrophages (such as raised serum ferritin levels and raised serum sCD163 levels) and of endothelium (such as thrombocytopenia and raised plasma VWF levels) need to be studied in COVID-19 patients across a spectrum of disease severity.

COVID-19 patients with less severe acute lung injury (organ dysfunction, before onset of organ failure) need to be selected for the treatment with low-volume PLEX and low-dose steroid. The window for this therapeutic intervention is likely to be narrow and needs to be defined in appropriately designed studies.

Acknowledgment

We gratefully acknowledge the technical inputs and support from Dr. Shibu Jacob, Nephrology Department, and Dr. Dolly Daniel and Dr. Joy Mammen, Transfusion Medicine and Immunohaematology Department, Christian Medical College Hospital, Vellore, India, for providing PLEX therapy for acutely ill patients in liver failure.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 Supplementary Material



Low-volume plasma exchange (PLEX) and low-dose steroid to treat acute liver injury/failure OR acute-on chronic liver failure: The Vellore Protocol

Indications

Acute liver injury/failure±other vital organ injury/failureSecondary hemophagocytic lymphohistiocytosis (HLH) (serum ferritin≥500 ng/mL)[1]Endothelial activation (raised plasma von Willebrand factor [VWF] levels).

Contraindications

Recent major bleed (gastrointestinal, intracranial, pulmonary, intravitreal, etc., in the last 2 weeks. As VWF is a blood clotting protein, we are concerned about precipitating further bleeding by VWF depletion)Ongoing sepsisHemodynamic instability after appropriate resuscitation and vasopressor support of>0.5 mcg/kg/min of noradrenaline or a second vasoactive drug to maintain a mean arterial pressure of 65 mmHg.

Procedure

Patients are admitted to a monitored setting (high-dependency unit/ITU)Obtain patient/next of kin consent after counseling about all other treatment optionsFemoral vein is our preferred access for PLEX port insertion under ultrasound guidance.[2] This access is exclusively for PLEX and not used for any other reason (e.g. obtaining blood samples, administering medicines). We do not use prophylactic platelet transfusion for line insertionWe avoid sedation (to reduce need for mechanical ventilation and risk of precipitating encephalopathy). Patients at risk of aspiration or who develop respiratory failure are intubated on a case-by-case basisWe do not give prophylactic platelet transfusions. In case of need for platelet transfusion to cover for an invasive procedure, we give fresh frozen plasma infusions (to supplement ADAMTS13) before giving platelet concentratesIt is preferable to avoid invasive diagnostic tests, until this treatment is completedWe give empiric antibiotic after blood cultureTablet Prednisolone 10 mg or equivalent is started as soon as decision to PLEX taken and continued for at least 1 week after stopping PLEX. Longer duration (up to 4 weeks) of steroids, if needed, may be given after reassessing the patient™s overall conditionPlasma volume is estimated by Kaplan method[3] [0.065 × weight (kg)] × (1 − hematocrit). We target 50% of plasma volume to be exchanged per the PLEX session. In case of major bleed (2–4 weeks ago)/treated sepsis/significant hemodynamic instability, 25% of plasma volume is exchangedThe replacement fluid is fresh frozen plasma at 1:1 volume (so that the pheresed plasma does not render the patient immune depleted and more prone to sepsis. In addition, ADAMTS13 in the infused fresh frozen plasma has a VWF-lowering effect).Centrifugal-type PLEX is preferred to membrane-type PLEXPLEX is done daily and three sessions targeted; the decision on performing PLEX is to be reviewed each day; the total number of sessions of PLEX is decided based on tolerability/patient™s clinical condition. During PLEX, strict asepsis/avoid hemodynamic instability/give adequate calcium supplementation. Remove port as soon as need for PLEX is overInfection surveillance: We do daily surveillance blood culture on days of PLEX. In case of bacteremia/clinical signs of worsening sepsis while on PLEX, withhold/discontinue PLEX until sepsis is controlled.N-Acetyl cysteine[4] (as a VWF-lowering measure, oral or intravenous) and oral zinc (aimed to reduce gut permeability) are also given for 2–4 weeksOrgan-specific standard of care for critically ill patient to continue.

References (for Supplementary Material–PLEX Protocol)

La Rosée P, Horne A, Hines M, von Bahr Greenwood T, Machowicz R, Berliner N, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:2465-77.Patel L, Jacob S, Mathews N, Mammen J, Nair SC, Vijayalekshmi B, et al. Plasma exchange therapy in liver failure: Femoral port insertion may be preferable Indian J Gastroenterol 2018;37(Suppl 1):A79 Abstract # 259.Kaplan AA. A simple and accurate method for prescribing plasma exchange. ASAIO Trans 1990;36:M597-9.Chen J, Reheman A, Gushiken FC, Nolasco L, Fu X, Moake JL, et al. N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. J Clin Invest 2011;121:593-603.

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