Takotsubo cardiomyopathy secondary to haemophagocytic lymphohistiocytosis in HIV patients: a comprehensive review

Abstract

Haemophagocytic lymphohistiocytosis (HLH) is an immune dysregulation disorder with variable presentations and non-specific features making it extremely difficult to diagnose early in the clinical course. Here, we are presenting a case of a young man who presented in cardiogenic shock with findings of anterolateral wall ischaemia on ECG. Echocardiography findings were consistent with takotsubo cardiomyopathy (TCM). Cardiac catheterisation showed clean coronary arteries and pulmonary artery pressure measurements showed high output cardiac failure. After extensive workup, the patient was diagnosed with HLH. In spite of aggressive supportive and definitive therapy, he eventually died due to a complicated clinical course. We did a comprehensive literature review and found that this is the first reported case of HLH presenting as TCM as the initial clinical manifestation.

Background

Haemophagocytic lymphohistiocytosis (HLH) is characterised by hyperproliferation of macrophages secreting excessive amounts of inflammatory cytokines leading to immune dysfunction and multisystem organ failure. Most commonly it presents with fever, cytopaenias and hepatosplenomegaly, but many other unusual presentations have been described in the literature. It has been reported in association with infections, malignancy and many autoimmune disorders. Our case was unique, where a young patient presented in cardiogenic shock secondary to HIV-related HLH.

Case presentation

A 32-year-old otherwise healthy Caucasian man was brought to the emergency department (ED) after found unresponsive at home with agonal breathing and cold, mottled extremities. According to his parents, he had exertional shortness of breath, nocturnal cough and lethargy for at least 2 weeks before presentation. He was propping up his bed at night to sleep comfortably. He was denied a commercial driving licence after he was found to have haematuria and proteinuria on his urinalysis 2 weeks ago, but no further details were available. The renal function at that time was normal. Parents reported weight loss of about 20 lbs over the past 2 months. He had an unsubstantiated history of HIV infection of unknown duration and was not taking any medications. His parents denied any other medical history. He was an occasional alcohol drinker. They reported no history of intravenous drug use or smoking.

Initial ED vitals showed a blood pressure of 84/48 mm Hg, heart rate of 118 bpm, respiratory rate of 25/min with oxygen saturation unable to be obtained and a temperature of 37.5°C. Physical examination revealed that he was in acute respiratory distress on bag valve mask ventilation, cyanotic and had mottled extremities. He was normocephalic and non-traumatic. The neck was supple with no visible jugular venous distension. Pupils were equal and reactive to light. Oral examination was unremarkable. Lungs were clear to auscultation bilaterally. Heart sounds were normal with no murmurs appreciated. Abdomen was soft, non-tender but distended; bowel sounds present. There was no pedal oedema. There was no scleral or skin icterus, or jaundice. Neurological examination showed eye-opening to pain only, verbal response absent and withdrawing to pain on motor examination with Glasgow Coma Scale of 7/15.

Investigations

ECG was consistent with anterolateral wall ischaemia with deep T-wave inversion in the precordial leads (figure 1). No prior ECGs were available for comparison. An urgent echocardiogram (ECHO) in our hospital showed severe global hypokinesis of the left ventricle (LV) with an ejection fraction of 10%–15% and normal LV thickness. The right ventricle (RV) was mildly dilated and RV function moderately reduced. (video 1 and figure 2). Emergency left and right heart catheterisations (LHC and RHC) were performed. RHC findings showed mildly elevated filling pressures with no intracardiac shunting. Surprisingly, cardiac output and cardiac index were found to be high (figure 3). These findings are summarised in (table 1). LHC showed normal coronaries. These findings were consistent with high output cardiac failure although no apparent cause was suspected.

Figure 1.

ECG showing deep T-wave inversion in precordial leads suggestive of possible anterolateral wall ischaemia.

Video 1.

Download video file ^{(227.2KB, mp4)}

DOI: 10.1136/bcr-2018-226599.video01

Global hypokinesia seen on echocardiography with some right ventricle dilatation and small pericardial effusion. 2D, two dimensions.

Figure 2.

Severe global hypokinesia of left ventricle on echocardiography with some right ventricle dilatation.

Figure 3.

Normal coronary arteries on cardiac catheterisation.

Table 1.

Table showing the right heart catheterisation (RHC) and laboratory findings on presentation

Laboratory values	Patient’s value (normal range)	RHC	Patient’s value (normal range)
Haemoglobin (g/L)	11.4 (12–16)	Right atrium Mean	24/21 (7/2) 17 (4)
White cell count	19 x109/L (4000–12 000)	Right ventricle	44/4 (24/4)
Platelet count	72x109/L (140 000–400 000)	Pulmonary artery Mean	43/12 (24/10) 28 (16)
Thyroid-stimulating hormone	90.9 (0.35–5.50 uIU/mL)	Pulmonary artery wedge (pulmonary capillary) Mean	26/27 (16/6) 20 (9)
Serum triiodothyronine T3	50 (80–180 ng/dL)	Left ventricle systolic end diastolic	128/10 (130/7) 20 (7)
Serum thyroxine (T4)	Total 0.2 (4.6–12 μg/dL), Free <0.1 (0.7–1.9 μg/dL)	Systemic venous resistance (dyn.s/cm5)	410 (700–1600)
Random cortisol (μg/dL)	46.3 (2.9–17.3)	Cardiac output (Fick’s) L/min	17 (4–8)
Adrenocorticotrophic hormone (pg/mL)	28 (7.2–63)	Cardiac Index (L/min/m2)	9.53 (2.4–4)
D-dimer (ng/mL, DDU)	>5250 (<230)	Mixed venous oxygen saturation (%)	83 (65–70)
Bicarbonate (mmol/L)	7 (20–31)	Chemistry	Patient’s value (normal range)
Aspartate transaminase (units/L)	8383 (4–34)	Lactic acid (mEq/L)	13.2 (0.5–2.3)
Alanine transaminase (units/L)	3645 (<55)	Glucose (mg/dL)	29 (70–100)
Alkaline phosphatase (units/L)	280 (40–150)	Sodium (mmol/L)	137 (135–145)
Total bilirubin (mg/dL)	2.6 (0.2–1.2)	Potassium (mmol/L)	6.7 (3.5–5.1)
Albumin(mg/dL)	2.8 (3.3–4.7)	Chloride (mmol/L)	98 (98–110)
Brain natriuretic peptide (pg/mL)	1883	Phosphorus (mg/dL)	10.2 (2.3–4.7)
Anion gap	32(8–12)	Blood urea nitrogen (mg/dL)	28 (<23)
Cardiac troponin (ng/mL)	3.32 (<0.10)	Creatinine (mg/dL)	2.70 (<1.11)
International normalised ratio	1.9 (0.8–1.1)	Activated partial thromboplastin time (seconds)	44 (22–35)

Laboratory findings were significant for an elevated white cell count (WCC), lactic acidosis, high troponin levels, hyperkalaemia, raised creatinine levels and severe high anion gap acidosis (table 1). Cultures, including urine, blood and sputum culture, were sent. Urine drug screen was negative for cocaine, opiates, phencyclidine and cannabinoids. Serum drug screen showed blood alcohol levels of 15 mg/dL (normal <10 mg/dL) but was otherwise unremarkable for salicylates and acetaminophen. CT head was negative for intracranial bleed. Chest X-ray showed moderate cardiomegaly with possible left-sided pleural effusion. (figure 4)

Figure 4.

Moderate cardiomegaly with some pleural effusion.

The patient had an HIV test done that showed a positive HIV antibody and a viral load of 170, 170 copies/mL. The absolute CD4 count was 6 μL (normal 359–1519/μL) Mycobacterium tuberculosis cultures, Epstein-Barr virus (EBV) comprehensive antibody panel, EBV PCR, cytomegalovirus PCR, toxoplasmosis antibodies and cryptococcal serum antigen were negative. Lumbar puncture was deferred due to ongoing coagulopathy. Haemolytic anaemia was ruled out by lack of spherocytes on the peripheral smear and negative direct Coombs test.

Due to multiorgan dysfunction syndrome, in the background of cytopaenia and severely elevated ferritin, HLH was considered as a diagnosis. A bone marrow biopsy was done which showed marrow cellularity at 40%. Marked dyserythropoiesis with accessory lobes and multinucleation was seen. Scattered histiocytes were noticed with rare histiocytes undergoing hemophagocytosis. Myeloid maturation and megakaryocyte distribution were unremarkable.

Differential diagnosis

A broad differential diagnosis was considered including septic shock, cardiogenic shock from myocardial infarction (MI), HIV-associated cardiomyopathy, cardiomyopathy from other causes, myxoedema coma, haemochromatosis-related cardiomyopathy, adrenal insufficiency and drug overdose, among others. But his echocardiography findings, normal catheterisation and negative drug screening excluded other causes and HLH-induced takotsubo cardiomyopathy (TCM) was confirmed eventually by complementary findings of bone biopsy.

Treatment

He was intubated due to haemodynamic instability and for protection of airway and then was managed in cardiac critical care unit with aggressive ventilatory support. At intubation, he was placed on an fractional inspired oxygen of 100%, tidal volume of 500 mL, respiratory rate of 14 and a peak end expiratory pressure (PEEP) of 5.0. Arterial blood gas (ABG) at that point showed a PH of 7.10, partial pressure of carbon dioxide of 31, partial pressure of oxygen of 230 and arterial oxygen saturation of 98%. He was initially started on intravenous thyroxine and steroids for suspicion of myxoedema coma. He required pressor support with norepinephrine and an intra-aortic balloon pump (IABP). Anuria, hyperkalaemia and severe metabolic acidosis led to continuous renal replacement therapy. Broad-spectrum antibiotics, including vancomycin, cefepime and levofloxacin, were started for the suspicion of septic shock. Once the opportunistic infections were ruled out and CD4 count and HIV viral load were available, antiretroviral therapy with abacavir, lamivudine and dolutegravir was started, along with prophylaxis with atovaquone and azithromycin for pneumocystis pneumonia and Mycobacterium avium intracellulare, respectively. Trimethoprim–sulfamethoxazole and dapsone were not considered due to pancytopenia, renal insufficiency and suspicion of haemolysis. The multidisciplinary care team was involved in his care.

Later in the day, he developed bleeding from the nasogastric tube. He was already on stress ulcer prophylaxis with injectable pantoprazole which was changed to intravenous infusion. Ultrasound of the liver showed hepatomegaly (20 cm) and fatty infiltration with moderate to massive ascites. The spleen measured at 13 cm, consistent with moderate splenomegaly. Repeat laboratory evaluation the next day is shown in table 2.

Table 2.

Repeat laboratory findings during hospital stay

Laboratory Values
Laboratory values	At 0 hour	After 6 hours	After 12 hours
Haemoglobin (g/L)	11.4	9.5	8.1
Platelet	72x109/L	58 000	54 000
White cell count	19x109/L	13 000	6500
International normalised ratio	1.9	2.5	3.0
Fibrinogen (mg/dL)	251	187	168
Ferritin (ng/mL)		>40 000
Serum Iron (µg/dL)		204
Total Iron binding capacity		Unable to be calculated
Lactate dehydrogenase (LDH)(U/L)		>7500
Troponin (ng/mL)	3.32	7.40	12
Creatine kinase (U/L)	267	670	1608
Retic count (%)		4.4
Haptoglobin (mg/dL)		<8

Hepatomegaly and ascites prompted checking hepatitis serologies and iron studies. Hepatitis A, B and C serologies were negative. Worsening anaemia and thrombocytopaenia in the presence of relatively low fibrinogen and high D-dimer raised the possibility of disseminated intravascular coagulation (DIC). He was given 10 mg of intravenous vitamin K and low-dose heparin at 300 units/hour for the management of coagulopathy and DIC. The patient was ultimately diagnosed with HLH based on the criteria set forth by HLH-2004 trial, by meeting at least six out of eight findings including fever, splenomegaly, bicytopenia, hypofibrinogenaemia, hyperferritinaemia and bone marrow biopsy showing hemophagocytosis. Dexamethasone 2 mg every 6 hours and renal clearance adjusted etoposide were started as definitive therapy for HLH as a last resort.

Outcome and follow-up

Repeat ECHO was normal and showed complete reversal of LV hypokinesia and RV dilatation suggesting that it was a stress induced event. Free thyroxine normalised after one dose of levothyroxine and his presentation was also not found to be consistent with myxoedema coma. He had a complicated clinical course with prolonged haemodynamic instability and intermittent requirements for inotropic support after removal of IABP. He required multiple transfusions of red cell count, platelets and fresh frozen plasma over the course of his stay. After 16 days course of protracted illness without any meaningful progress, the family decided to opt for comfort care, he was palliatively extubated and died.

DISCUSSION

HLH is an elusive haematological disorder with a wide array of clinical presentations and multisystem involvement which not only makes it challenging to diagnose but hard to manage. Its worldwide incidence is not well reported in adults. However, about 1.2 million children are affected by HLH each year.¹ Traditionally, HLH was characterised into primary and secondary HLH, primary being due to genetic causes which usually occurs at early age and is rare later in life. Secondary HLH occurs with from viral infections (prevalence being 29%), followed by bacterial, fungal and protozoal infections (20%), malignancies (27%), autoimmune disease (7%) and immunodeficiency (6%).² HIV is rarely reported in association with HLH, and mostly it is the opportunistic infections or the malignancies that are the precipitating event for HLH. However, it is argued that HIV might play a role in activation of HLH by itself.³ Our case was unique regarding its presentation and its association with HIV in the absence of any malignancy or opportunistic infections.

HLH is a disease of hyperinflammation characterised by uncontrolled proliferation of activated lymphocytes and macrophages that secrete excessive amounts of inflammatory cytokines and by the inability of the natural killer cells and cytotoxic T-cells to downregulate the immune response.¹ This leads to immune dysregulation by inducing apoptosis in themselves and other elements at the forefront of the immune response such as macrophages after a threat is neutralised. Continued stimulation and prolonged survival of immune cells lead to the excessive release of cytokines and proinflammatory markers like TNF-alpha, IL-2, IL-1β and IL-6. IL-2 and its receptor CD-25 have a diagnostic role in the HLH criteria and has been an important indicator of increased T-cell activity. However, the mechanism of pathogenesis by these markers is unknown.¹ This mechanism explains the multisystem organ failure, high morbidity and mortality associated with HLH.¹ Our patient also had classic multisystem involvement with the unique cardiac involvement, causing globular hypokinesis and presenting as TCM.

TCM is stress-induced cardiomyopathy defined as a temporary but severe ventricular dysfunction in the presence of new ECG changes, but normal coronary arteries on cardiac catheterisation. TCM is most commonly reported in people with emotional and physical stress with extreme sympathetic stimulation which leads to a barrage of catecholamine release leading to focal LV dysfunction, mostly apical or mid-wall segments and rarely global hypokinesis.⁴ TCM is commonly reported in patients with sepsis and in critically ill non-septic patients. What causes TCM in HLH is unclear. However, the role of inflammatory cytokines, such as TNF-alpha, IL-1β and IL-6, has been implicated in the pathogenesis of TCM among other mechanisms, and this might be the possible cause of TCM in HLH patients. Only one previous case of TCM related to HLH was reported where the patient developed HLH on the 12th day of hospitalisation and patient had apical hypokinesis.⁴ Our patient, however, had TCM on presentation with global hypokinesis instead of apical hypokinesis, making it an extremely rare presentation. These changes were transient and resolved, once the trigger of HLH was addressed.

To establish the link between this unusual association, we performed a structured Medline search and found only nine reported cases of cardiac complications associated with HLH.^4–12 Most of these cases were reported in children (five in nine) with only three cases reported in adults. Almost all patients presented with fever except two who presented with dyspnoea. Myocarditis was diagnosed in four instances although biopsy was available in only one case for confirmation. TCM was diagnosed in one other case in addition to ours who presented with fever and fatigue in contrast to our patient. It is interesting to note that in two instances HLH-associated complication was hypertrophic obstructive cardiomyopathy. Most patients eventually recovered. None of the cases reported had HIV as the inciting event for HLH and none of them presented as a cardiogenic shock with global hypokinesis. The characteristics of these patients are shown in table 3.

Table 3.

Characteristics of previously reported cases of cardiac complications in association with HLH

Age/gender	6/Female	4/Female	8/Female	6 weeks/Female	10/Female	28/Male	40/Female	17/Female	7/Male
Country	USA	Japan	China	Oman	India	India	Japan	Greece	Czech republic
Publication year/reference no	2014/4	2016/5	2016/6	2015/7	2011/8	2009/9	2006/10	2006/11	2002/12
Presenting symptoms	Fever/fatigue	Fever	Fever/ecchymosis	Fever/abdomen distension	Fever/chills/vomiting	Fever/SOB	SOB	Cardiogenic shock	Fever
Cardiac complications	Stress cardiomyopathy/takotsubo	Myocarditis with thickened LV and CA aneurysm	Second degree atrioventricular (AV) block and ST depressions	Hypertrophic obstructive cardiomyopathy (HOCM)	Myocardial dysfunction EF 25%	Myocarditis	Myocarditis	Myocarditis	HOCM
DOA at dx of cardiac complication	Day 12	Day 19	Day 2	Week 4	-	Autopsy	Day 12	Presentation	5 weeks
Association	UTI/bactrim	EBV	EBV	Genetic	Plasmodium falciparum	Parvovirus B19	Influenzae virus	Enterovirus	Leishmaniasis
Diagnosis	Echo with apical akinesia	ECHO myocardial thickness and elevated trop and CK	ECG	ECHO, HOCM, ECG	ECHO, Myocardial dysfunction	Autopsy	ECHO, global hypokinesia	ECHO	-
Outcome	Resolved	Resolved	Resolved	Death at 9 months	Resolved	Death	Resolved	Resolved	Resolved

CA, coronary artery; EBV, Ebstein-Barr virus; ECHO, echocardiogram; EF, ejection fraction; HLH, haemophagocytic lymphohistiocytosis; LV, left ventricle; SOB, shortness of breath; UTI, urinary tract infection.

HLH usually has non-specific presenting features but fever and high ferritin are present in almost all patients, while other integral features are hepatosplenomegaly, cytopaenia and high LDH1.¹ Diagnosis is made using the criteria devised by HLH-2004 trial as shown in box 1. According to this protocol, the determination of HLH is established if five out of eight diagnostic tests are met. These criteria include five initial clinical presentations.

Box 1. Diagnostic criteria devised by haemophagocytic lymphohistiocytosis (HLH-2004) trial.

For diagnosis of HLH, either one or both of the following criteria should be met.

A. Genetic diagnosis

or

B. Five of the following eight diagnostic criteria

1. Fever.

2. Splenomegaly.

3. Cytopaenias (at least 2 of the following lineages).

   • Haemoglobin <9 g/dL.

   • Neutrophils <1×${\displaystyle {10}^3}$/mL.

   • Platelets <100×${\displaystyle {10}^3}$/mL. Hypofibrinogenaemia (<150 mg/dL) and/or hypertriglyceridaemia (fasting, >265 mg/dL).

4. Hemophagocytosis found in bone marrow, lymph nodes, liver or spleen.

5. Ferritin levels >500 ng/mL.

6. Decreased or non-existent natural killer cell activity.

7. Increased levels of soluble CD25 >2400 U/mL.

Our patient met six out of nine characteristic parameters (fever, splenomegaly, bicytopenia, hyperferritinaemia and hemophagocytosis in the bone marrow). It is important to note that these criteria were originally devised for children but many case reports have applied the same criteria for adults as there are no defined guidelines for adults.¹

Once the diagnosis of HLH is suspected, attempts should be made to find the aetiology among the above-mentioned secondary causes as HLH in adults is usually due to associated conditions, and HLH due to genetic causes usually presents in the first year of life.¹ Our patient was too old for genetic HLH and had no signs or laboratory evidence of viral, bacterial or protozoal infections. Similarly, the autoimmune disease and malignancy workups were negative, ruling out secondary causes of HLH. Our patient first presented with TCM in cardiogenic shock and was later diagnosed with HLH. In 2017, Manji et al reported 10 cases of acute HIV infection presenting as HLH, some presenting with bloody diarrhoea, sepsis or pulmonary symptoms. But our case is unique due to the fact that the patient presented with cardiogenic shock and was later found to have TCM.¹³ These findings indicate that patients with HLH can present with variable signs and symptoms depending on the involved organ failure.

HLH treatment should begin as soon as possible once there is a high index of suspicion without having to wait for genetic or immunological results. Not all patients can fulfil the criteria set forth by HLH-2004 protocol and consultation with a haematologist familiar with HLH is imperative.¹⁴ It is important to note that some patients can have increased cell counts, especially the WCC on presentation, and there is a rapid decline in the cell lines within a few hours or days, as was the case in our patient.¹⁵ Supportive care is given with as needed blood products transfusions. Diagnosis and treatment of opportunistic infections is also very important. The mainstay of HLH treatment is immunosuppressive drugs including dexamethasone and etoposide according to HLH-2004 protocol. Intrathecal methotrexate and hydrocortisone are considered for patients with neurological manifestations. Unfortunately, even on definite therapy, many patients have dynamic clinic course mandating adjustment of the regimen and have a median survival of only 50%.¹⁶ Conflicting data is present in the literature regarding the use of etoposide and dexamethasone. Some studies have proved an increased 5-year survival rate with this therapy in comparison to ciclosporin while other studies have conflicting results. The latest study by Bergsten et al in more than 300 patients with HLH compared, they reported more than 54% survival in patients treated with etoposide and dexamethasone, while early introduction of other therapies like cyclosporine did not improve HLH outcome in patients treated with etoposide–dexamethasone.¹⁷ Owing to the fact that CD 25 has a role in HLH, daclizumab, a monoclonal antiCD25 antibody was reported to be successful as well, but more studies are needed to establish the fact.¹⁸

Learning points.

• Haemophagocytic lymphohistiocytosis (HLH) is a rare and difficult to diagnose disease due to heterogeneous and non-specific presentations. Delay in diagnosis is one of the most critical factors in its high mortality and morbidity.

• Takotsubo (stress) cardiomyopathy (TCM) in non-septic critically ill patients in the background of liver dysfunction, cytopaenia and elevated inflammatory markers should raise suspicion of HLH.

• Effort should be made to identify the underlying trigger of HLH such as infection, malignancy or autoimmune diseases.

• If expertise for treating HLH is lacking at a facility, arrangements should be made to transfer the patients to centres with appropriate resources available.

• HIV may be able to precipitate TCM in a setting of HLH, and this should be one of the differentials in mind when encountering such patients.