Keywords
Hemophagocytic Lymphohistiocytosis (HLH), Copper Sulphate, Immune-mediated, Intravascular hemolysis, Acute Kidney Injury
This article is included in the Manipal Academy of Higher Education gateway.
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.
Hemophagocytic Lymphohistiocytosis (HLH), Copper Sulphate, Immune-mediated, Intravascular hemolysis, Acute Kidney Injury
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.
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.
Serial investigations are tabulated in Table 1.
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.11–13
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.
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Is the background of the case’s history and progression described in sufficient detail?
Yes
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?
Partly
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?
Yes
Is the case presented with sufficient detail to be useful for other practitioners?
Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Sepsis/ Shock/ ARDS/ Extra corporeal therapies
Is the background of the case’s history and progression described in sufficient detail?
Yes
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?
Yes
Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?
Yes
Is the case presented with sufficient detail to be useful for other practitioners?
Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: hematological disorders and HLH
Alongside their report, reviewers assign a status to the article:
Invited Reviewers | ||
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Version 1 23 Apr 24 |
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Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list:
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