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Case Report

Case Report: Copper sulphate related hemophagocytosis with lymphohistiocytosis

[version 1; peer review: 2 approved]
PUBLISHED 23 Apr 2024
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This article is included in the Manipal Academy of Higher Education gateway.

Abstract

Abstract*

The accidental, suicidal, and homicidal toxicities of copper sulfate have been extensively documented. The later stages of the disease demonstrate signs of systemic toxicity, characterized by intravascular hemolysis, oliguric renal failure, convulsions, and circulatory collapse. Despite the extensive description of life-threatening intravascular hemolysis, Hemophagocytic Lymphohistiocytosis (HLH) related to copper sulfate poisoning has not been described.

A 45-year-old male presented with accidental consumption of copper sulfate. Laboratory evaluation revealed leukocytosis, intravascular hemolysis, acute liver injury, acute kidney injury, severe metabolic acidosis, and hyperkalemia. The patient was shifted to the Intensive Care Unit and hemodialysis was initiated. On the 9th day, he developed high-grade fever with chills. With the suspicion of a central line-associated bloodstream infection, empirical antibiotic therapy was initiated, and the lines were revised. On the 19th day, the high-grade fever recurred. Investigations revealed trilineage cytopenias. With a high degree of suspicion for HLH, further investigations revealed increased ferritin levels. Bone marrow aspiration cytology showed evidence of reactive marrow with haemophagocytic lymphohistiocytosis. The patient was initiated on corticosteroid therapy, after which symptomatic and laboratory recovery was noted.

Although copper sulfate poisoning is potentially fatal in large quantities, few studies have examined the possible immune-mediated abnormalities in individuals. Owing to the direct membranolytic effect of copper sulfate, it is not unreasonable to have immune-mediated organ damage. To the best of our knowledge, this is the first report of Hemophagocytic Lymphohistiocytosis attributed to copper sulfate intoxication.

The present case demonstrates that the diagnosis of HLH must be considered when treating a case of copper sulfate poisoning; however, the exclusion of the most common complications must be first established.

Keywords

Hemophagocytic Lymphohistiocytosis (HLH), Copper Sulphate, Immune-mediated, Intravascular hemolysis, Acute Kidney Injury

Introduction

Acute copper intoxication is often the result of accidental consumption, suicide, or homicidal attempts. Bordeaux mixture, a copper-based fungicide used in agricultural practice, is widely available in the Indian sub-continent.1,2 Ingestion of more than 1 g of copper sulfate results in manifestations of symptoms while–20 g may be lethal.3,4 The clinical manifestations of toxicity predominantly involve erosive gastropathy, hepatitis, acute kidney injury, rhabdomyolysis, convulsions, circulatory collapse, and haematological complications.5

The major haematological manifestations include intravascular Haemolysis and Methemoglobulinemia.5 Intravascular hemolysis often starts as early as 12-24 hours after ingestion of the substance owing to the direct membranotoxic and oxidative stress caused to the erythrocyte membrane, whereas methemoglobinemia occurs because Cu2+ ions oxidize Fe2+ in hemoglobin to Fe3+.6 Although these two manifestations have been described extensively in the literature, the occurrence of Hemophagocytic Lymphohistiocytosis (HLH) due to copper sulfate ingestion has not been described.

HLH is a disease of multi-organ dysfunction that can have extremely nonspecific presentations.7 These include prolonged fever, cytopenia, hepatosplenomegaly, liver dysfunction, and neurological dysfunction.8 The broad range of presentations and lack of specificity make the diagnosis of HLH quite challenging, requiring the ruling out of alternative diagnoses.7

Herein, we describe a case of Hemophagocytic Lymphohistiocytosis attributed to accidental copper sulfate poisoning.

Case report

A male in his 40s with an unremarkable medical history was referred to our center with an accidental, alleged consumption of copper sulfate while under the influence of alcohol. He was treated at a nearby regional hospital with gastric lavage and intravenous fluids before referral. On reporting, the patient was conscious, well-oriented, and hemodynamically stable. Tachypnea, pallor, and icterus were also noted. Initial laboratory evaluation revealed anemia with a hemoglobin level of 12.6% and leukocytosis with a white blood cell count of 23500 cells/μL, evidence of hemolysis, acute liver injury, acute kidney injury, and severe metabolic acidosis with hyperkalemia. The patient was admitted to the Intensive Care Unit for further care.

The following day, his hemoglobin dropped to 6.9 gm%, the leukocyte count increased to 41400 cells/μL, and platelet count dropped to 1.01 lakh cells/μL. His serum creatinine elevated by 2.96 units and serum urea by 70 units above the baseline, suggesting worsening renal function owing to the extensive damage caused to the kidney by copper sulfate. Hyperkalemia persisted. The patient remained oliguric with increasing acidosis and was initiated on supportive hemodialysis. He underwent six cycles of hemodialysis during his hospital stay. Supportive blood transfusions were also started.

On the 9th day of hospitalization, the patient developed high-grade fever with chills. With suspicion of Central Line Associated Blood Stream Infection (CLABSI), he was started on empirical antibiotics following collection of appropriate cultures, and the lines were revised. No growth was observed in the culture medium. The patient continued to be dialysis dependent due to ongoing oliguric renal failure.

On the 19th day of hospitalization, a similar episode of high-grade fever with normal leukocyte counts recurred, along with anemia. A peripheral Smear was unremarkable. Blood cultures were resent, and the lines were revised. However, the fever persisted. As a result of persistent fever, investigations revealed trilineage cytopenia, and HLH was suspected. Targeted investigations have revealed increased serum ferritin and D-dimer levels. The bone marrow aspirate showed evidence of reactive marrow with Hemophagocytic Lymphohistiocytosis, as depicted in Figure 1. Repeated blood cultures were considered sterile. The patient was initiated on corticosteroids for HLH, following which his fever subsided, with improvement in cytopenia. Supportive care was then continued. Renal function tests showed gradual recovery with improved urine output. The dialysis sessions were gradually spaced, stopped, and then discharged. He was followed up as an outpatient until his kidney function normalized.

c68c64e3-0c6c-4b54-9689-c38a636244b9_figure1.gif

Figure 1. (A-F): Bone marrow aspirate: A: Highly cellular bone marrow particles (Leishman Stain; 40X). B: Increased marrow macrophages (arrow), many with pigment or engulfed cells (Leishman stain;100X). C: Hemophagocytic macrophages with evidence of cellular remnants within the cytoplasm (Leishman stain;400X). D: Active hemophagocytosis: Macrophage (encircled), has engulfed lymphocyte, erythroblast and neutrophils (Leishman stain;400X). E: Pigmented hemophagocyte (Leishman stain;400X). F: Increase in pigment-laden macrophages in the marrow (Leishman stain;1000X).

Serial investigations are tabulated in Table 1.

Table 1. Summary of laboratory findings.

DateHemodialysisHemoglobinTotal leukocyte countPlatelet countSerum creatinineBlood ureaSerum potassium
gm/dLcells/μLcells/μLmg/dLmg/dLmEq/L
23.07-12.6263002.29L1.49315.17
24.07-6.9414001.01L4.452005.2
25.07Yes5.21418000.79L9.25347
27.07Yes3.4289001.5L7.732384.47
29.07Yes6.9308501.4L6.84212
02.08Yes5219802.34L9.19212
07.08-4.847802.56L13.51875.53
08.08Yes6.531701.98L9.151153.81
10.08-5.953101.44L12.6137
12.08Yes8.529101.4L
18.08-9.6188401.4L9.6842
20.08-8.9116301.08L5.4548
24.08-7.744101.27L5.7277
29.08-3.997
10.09-10.286101.52L1.642

Discussion

Copper sulfate, a herbicide commonly used in agricultural practice in the Indian subcontinent, is commonly abused in suicidal or homicidal attempts.9 Following the initial symptoms of metallic taste, salivation, thirst, nausea, abdominal pain, recurrent vomiting, and painful diarrhea, signs of systemic toxicity appear, which are characterized by intravascular hemolysis, oliguric renal failure, convulsions, and circulatory collapse.

HLH, often described as a diagnostic conundrum, is a life-threatening manifestation of uninhibited activation of immune cells to secrete excessive amounts of cytokines, leading to tissue destruction and multi-organ failure.10 HLH can be of two types: familial and sporadic. The latter tends to occur with autoimmunity, malignancies, infection.8 Common clinical manifestations include prolonged fever, erosive gastropathy, hematemesis, melena, acute liver failure due to direct copper toxicity, hepatosplenomegaly, anuria following acute kidney injury, and neurologic dysfunction, such as seizures, ataxia, and paraplegia.5 Elevated serum ferritin, pancytopenia, deranged liver function tests, kidney function tests, elevated D-dimer, hypertriglyceridemia, and hypofibrinogenemia are laboratory abnormalities that should be considered when diagnosing HLH.1113

Here, we describe the case of a male in his 40s with an alleged accidental consumption of an unquantified amount of copper sulfate who developed features of HLH during his hospital stay. Although the presence of intravascular hemolysis-related complications, which occur as early as the first 12-24 hours have been extensively documented in copper sulfate poisoning, the occurrence of HLH has not been reported. Few studies have described possible immune-mediated abnormalities in individuals with copper sulfate poisoning.

On arrival, the patient experienced intravascular hemolysis, leukocytosis, acute kidney injury, acute liver injury, and severe metabolic acidosis with hyperkalemia. He underwent supportive transfusions and six cycles of hemodialysis. There are multiple factors contributing to the development of AKI in copper sulfate toxicity, including direct oxidative damage to the proximal tubules, hemoglobinuria, rhabdomyolysis, and pre-renal failure.14 Recurrent episodes of fever after repeated line revisions and culture negativity raised the suspicion of HLH. Bone marrow aspiration cytology and elevated D-dimer and ferritin levels confirmed the suspicion of HLH and specific treatment was initiated. The patient recovered with the normalization of renal function.

To the best of our knowledge, this is the first report of Hemophagocytic Lymphohistiocytosis attributed to copper sulphate toxicity. The present case demonstrates that HLH could be one of the differential diagnoses for fever in such patients, although it should be considered after the exclusion of common etiologies.

Ethical approval

Ethical approval not required.

Consent

Written informed consent was given by the patient.

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Ramachandra K, Reddy Narayana A, Srinivas S and H B S. Case Report: Copper sulphate related hemophagocytosis with lymphohistiocytosis [version 1; peer review: 2 approved]. F1000Research 2024, 13:326 (https://doi.org/10.12688/f1000research.147189.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Open Peer Review

Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 23 Apr 2024
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Reviewer Report 17 Oct 2024
Ajith Kumar, Aster Whitefield Hospital,, Bengaluru, Karnataka, India 
Approved
VIEWS 5
It is an interesting case report showing a temporal association of copper sulfate ingestion with the development of secondary HLH. The adapted 2004 HLH guidelines, & H- Score are important tools for helping clinicians arrive at secondary HLH diagnosis. The ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Kumar A. Reviewer Report For: Case Report: Copper sulphate related hemophagocytosis with lymphohistiocytosis [version 1; peer review: 2 approved]. F1000Research 2024, 13:326 (https://doi.org/10.5256/f1000research.161355.r328792)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 18 Oct 2024
    Koushik Ramachandra, Department of General Medicine, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India
    18 Oct 2024
    Author Response
    We thank you for reviewing our report Sir.
    1. As you have pointed out interactions between ethanol and copper sulphate could have set off an immune response. Though chemically,
    ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 18 Oct 2024
    Koushik Ramachandra, Department of General Medicine, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India
    18 Oct 2024
    Author Response
    We thank you for reviewing our report Sir.
    1. As you have pointed out interactions between ethanol and copper sulphate could have set off an immune response. Though chemically,
    ... Continue reading
Views
6
Cite
Reviewer Report 20 Jun 2024
Nur Soyer, Ege University, Izmir, Turkey 
Approved
VIEWS 6
The history and progression of the case is described in sufficient detail.  Sufficient detail is given about the physical examination and diagnostic tests, the treatment administered and its results.
There is sufficient discussion of the significance of the findings ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Soyer N. Reviewer Report For: Case Report: Copper sulphate related hemophagocytosis with lymphohistiocytosis [version 1; peer review: 2 approved]. F1000Research 2024, 13:326 (https://doi.org/10.5256/f1000research.161355.r288685)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 21 Jun 2024
    Koushik Ramachandra, Department of General Medicine, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India
    21 Jun 2024
    Author Response
    Thank you for reviewing our case report Dr. Nur Soyer.
    Competing Interests: None
COMMENTS ON THIS REPORT
  • Author Response 21 Jun 2024
    Koushik Ramachandra, Department of General Medicine, Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India
    21 Jun 2024
    Author Response
    Thank you for reviewing our case report Dr. Nur Soyer.
    Competing Interests: None

Comments on this article Comments (0)

Version 1
VERSION 1 PUBLISHED 23 Apr 2024
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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