Background

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory haematological condition that is often aggressive, particularly when not identified early. The mortality rate in adult patients is 26.5%–74.8%.1 The broad constellation of symptoms associated with HLH is similar to numerous other haematological, infectious, autoimmune and allergic aetiologies and can be easily misattributed to another condition. While HLH is rare, early identification and prompt initiation of treatment are critical. Recent guidelines describe patients with HLH syndrome as to encompass those who meet the HLH diagnostic criteria while defining patients with HLH disease as those in whom the immune dysregulation is their primary disease process.2 Optimal treatment, including the necessity for immune suppression, may differ depending on the aetiology and classification of HLH. The seminal HLH-94 and HLH-2004 trials provide the framework for how HLH is diagnosed and treated today.3 4 Our report presents the case of a patient who presented with multisystem organ failure shortly after beginning a course of trimethoprim/sulfamethoxazole (TMP/SMX) and was subsequently diagnosed with HLH. Medication-induced HLH is a rare entity without established protocols for treatment or large-scale reports of patient outcomes.

Case presentation

A male in his early 30s underwent an office-based incision and drainage of a perirectal abscess and was started on a 7-day course of TMP/SMX. On the second day following the procedure, he developed fever, chills, night sweats and a rash, which persisted and worsened until his presentation to the hospital 5 days later. On arrival to the emergency department, the patient was found to have a fever of 40.2°C (104.4°F). On physical examination, he was well appearing with a a faint, blanching and morbilliform rash on his trunk with extension to the proximal extremities. The perirectal abscess had largely resolved with no visible erythema or drainage and minimal scabbing and tenderness.

Investigations

Initial laboratory testing showed pancytopenia (white cell count 1.29 x 10⁹/L, haemoglobin 12.0 g/dL, platelets 89 x 10⁹/L). He had significantly elevated inflammatory markers (D-dimer 25 375 ng/mL and ferritin 19 350 ng/mL). He also had mild acute kidney injury, elevated liver enzymes and coagulopathy. Over subsequent days, many of these laboratory abnormalities significantly worsened, including the pancytopenia and aspartate aminotransferase and alanine aminotransferase levels. He had rising inflammatory markers and development of hypertriglyceridaemia (table 1). The initial peripheral smear showed rouleaux formation, rare schistocytes and atypical lymphocytes, with no blasts or dysplastic leucocytes. A CT chest/abdomen/pelvis with intravenous contrast showed hepatosplenomegaly without any significant lymphadenopathy. A bone marrow aspirate with immunohistochemical stains for CD163 showed increased macrophages with haemophagocytosis (figure 1).

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Figure 1

Haemophagocytosis in the bone marrow biopsy from our patient.

Differential diagnosis

The differential diagnosis included adult-onset Still’s disease, drug hypersensitivity syndrome or HLH syndrome secondary to an infectious, rheumatological or malignant condition.

Given the patient’s high fevers, elevated inflammatory markers and recent history of infection, infectious aetiologies for his presentation were initially considered as either the primary aetiology of the patient’s symptoms or as the trigger for HLH. The patient’s perirectal abscess had largely resolved and high-resolution contrast-enhanced CT imaging showed resolving inflammation. Blood cultures were drawn and serologies were sent for numerous viral, tick-borne and sexually transmitted illnesses including the following: 20 virus respiratory panel with COVID-19, IgM and IgG for Rocky Mountain Spotted Fever, Ehrlichia, Anaplasma and Babesia, Epstein-Barr virus (EBV) IgM antibody, EBV DNA quantitative PCR, Cytomegalovirus DNA quantitative PCR, HIV fourth generation assay and viral load, Neisseria gonorrhoeae and Chlamydia trachomatis nucleic acid amplification, hepatitis B surface antigen, hepatitis B core IgM, hepatitis A IgM. No infectious aetiology was identified by molecular diagnostic tests or cultures.

Once an infectious aetiology was ruled out, adult-onset Still’s disease was considered in light of his systemic illness, rash, elevated inflammatory markers and hepatosplenomegaly. Although our patient had pancytopenia, he did not have arthralgias or myalgias, which are often considered universal features of this disease.5 A type III or type IV hypersensitivity reaction including serum sickness, drug reaction with eosinophilia and systemic symptoms (DRESS), or Stevens-Johnson syndrome were possibilities as well, although the patient’s relatively benign rash would have been atypical. A haematological/oncological condition, including leukaemia or other malignancy, precipitating HLH was an initial possibility given the patient’s pancytopenia and hepatosplenomegaly; however, the bone marrow biopsy was negative for malignancy.

Our patient met 6 of 8 HLH-2004 criteria with an H-score of 239 consistent with a 98%–99% probability of HLH. Hereditary or genetic causes of HLH are another potential cause, commonly referred to as primary HLH. Testing for natural killer cell function, perforin expression and CD107a expression tests can be done in conjunction with mutation analysis to help identify these patients. However, given this patient’s age, lack of family history, relatively mild disease and rapid response to treatment, primary aetiologies were considered less likely.6 The negative workup for other secondary causes as well as a concomitant temporal association with the use of a new medication, and a presentation largely consistent with a systemic drug hypersensitivity reaction, made the diagnosis of HLH in this patient the most conceivable, likely triggered by the TMP/SMX itself.

Treatment

The patient was started on 10 mg/m² intravenous dexamethasone for presumed HLH. Soon after initiating steroids, he defervesced and clinically improved. Laboratory markers of inflammation trended down and his acute kidney injury and cytopenia resolved. He was discharged on a slow steroid taper with close outpatient follow-up for continued monitoring.

Outcome and follow-up

Five months following initial presentation, the laboratory markers of HLH had all resolved, with the exception of a persistent mild indirect hyperbilirubinaemia. Steroids were discontinued. No malignancy or other systemic condition were identified during the workup. The patient remains asymptomatic and has returned to his prior baseline.