Autoimmune haemolytic anaemia and haemophagocytic lymphohistiocytosis in an adolescent boy with tuberculosis: an unusual association

Introduction

Tuberculosis (TB) is known to manifest with a myriad of clinical manifestations, often posing a challenge for the clinician. Haemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal condition of immune dysregulation resulting from uncontrolled activation of T lymphocytes and macrophages. ¹ There are two major forms of the disease: primary or familial; and secondary. The latter may arise secondary to infections including mycobateria, inflammatory disorders, malignancies, immune disorders and drugs. ² TB may also associated with a Coombs positive autoimmune haemolytic anaemia (AIHA). ³ There are separate reports of HLH and AIHA associated with TB, but to the best of our knowledge, both entities in the same patient associated with TB have not been reported previously.

Case report

A 14-year-old, appropriately immunised, thriving boy presented with complaints of daily episodes of moderate to high grade fever for 40 days, non-productive cough and loss of appetite for 30 days, and anaemia requiring eight blood transfusions over the same period. There were no respiratory, gastrointestinal and central nervous system symptoms. The past history was unremarkable. Initially, oral medications were given with no relief. Subsequently, on investigation, a positive Mantoux test (10 mm) and a chest radiograph showing paratracheal adenopathy (Figure 1a) were found. Sputum was, however, twice negative for acid fast bacilli (AFB). Nonetheless four-drug category 1 anti-tubercular therapy (ATT) was commenced, but discontinued by his parents after 5 days. Further consultations were sought and a thoraco-abdominal computed tomography (CT) scan was carried out, but symptoms persisted with repeated requirement of blood transfusions. OPEN IN VIEWER

On referral to our tertiary centre, the child was haemodynamically stable with no evidence of respiratory distress. There was pallor with insignificant cervical lymphadenopathy but no icterus. He had an enlarged liver and spleen. The remaining systemic examination was unremarkable. Serial full blood counts and liver function tests are shown in Table 1. The peripheral smear showed normocytic, normochromic anaemia, and a reticulocyte count of 4.5% with no abnormal cells. The direct Coomb’s test (DCT) was positive (2+) but the indirect Coomb’s test (ICT) was negative; the serum lactate dehydrogenase (LDH) was high (18.8 µkat/L), with a low serum haptoglobin (<3 mmol/L), suggesting a diagnosis of AIHA. ⁴ The renal function parameters were within normal limits. Review of the CT scan performed previously showed enhancing mediastinal lymph nodes with central areas of hypodensity suggestive of necrosis (Figure 1b) with a normal lung parenchyma. Diagnostic possibilities of Hodgkin’s lymphoma with autoimmune haemolytic anaemia, lymphoma with bone marrow involvement and TB with autoimmune haemolytic anaemia were considered, and further investigations were carried out accordingly. Bone marrow aspiration and biopsy revealed normal haematopoiesis with no granuloma, AFB, fibrosis or haemophagocytes. An initial biopsy from the mediastinal mass revealed predominantly necrosis with ill-defined granuloma, and no eosinophils, Reed-Sternberg cells or AFB. The biopsy was repeated, and this time AFB (Figure 2) were found. A diagnosis of mediastinal TB with AIHA was therefore concluded. Category 1 ATT, with Rifampicin, Isoniazid, Ethambutol and Pyrazinamide, was recommenced, together with prednisolone 2 mg/kg/day. Two days subsequently, jaundice with elevated transaminases but normal serum alkaline phosphatase ensued (Table 1), which was attributed to ATT. The treatment regime was thus modified to Ethambutol, Streptomycin and Levofloxacin. Markers of viral hepatitis (Anti-HAV IgM, Anti-HEV IgM, HBs Ag and Anti-HCV IgM), HIV (Human immunodeficiency virus) and auto-immune hepatitis (anti-nuclear antibody and anti-smooth muscle antibody) were negative. One day later, a pancytopenia (Table 1) emerged. Possibilities of auto-immune cytopenia, bone marrow fibrosis secondary to TB, ATT drug induced cytopenia, sepsis and HLH secondary to TB were entertained. The blood and urine cultures were sterile and the C-reactive protein was 15.2 nmol/L, thus ruling out sepsis. A repeat peripheral smear and bone marrow examination showed no evidence of malignancy. However, with a high ferritin (4943 pmol/Lng/mL), low fibrinogen (4.14 µmol/L) and reduced NK (natural killer) cell activity, our patient fulfilled six out of eight criteria for a diagnosis of HLH, namely, fever, splenomegaly, bicytopenia or pancytopenia, hyperferritinaemia, hypofibrinogenaemia and reduced NK cell activity. HLH was considered to be secondary to TB and so corticosteroid therapy was changed to dexamethasone 10 mg/m²/day in four divided doses together with supportive care for cytopenia, while modified ATT was continued. Marked improvement of blood counts was seen with no requirement for further blood transfusions. Likewise, liver function tests also improved over the next 3 days. The fever settled and our patient could be discharged after 5 days. OPEN IN VIEWER

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Table 1.

Serial investigations (complete blood count and liver function parameters) of the patient.

Date	Hb (g/L)	TLC (109/L)	DLC	Platelet (109/L)	TSB/ conj (µmol/L)	SGOT (µkat/L)	SGPT (µkat/L)	TP/Albumin (g/L)	SAP (µkat/L)
Before admission	88	8.10	N52 L40 M7 E1	166	6.84	0.53	0.53	71/40	4.02
21/04/15	76	4.95	N47 L37 M10 E6	156	46.18/2.08	3.11	1.62	58/30	5.71
24/04/15	65	1.00	N32 L56 M8 E4	29	29.08/17.10	2.59	1.37	53/28	4.78
27/04/15	80	1.30	N54 L41 M3 E2	65	11.97/8.55	1.85	1.40	68/31	4.07
29/04/15	89	2.20	N62 L30 M5 E3	106	8.55/3.42	0.94	1.12	67/37	3.61
21/05/15	108	3.33	N52 L38 M7 E3	182	10.26/3.42	0.57	0.27	72/39	4.02
11/06/15	109	4.21	N49 L39 M17 E5	289	8.55/3.42	0.58	0.23	70/39	2.56
08/07/15	125	6.35	N54 L35 M6 E5	246	–	–	–	–	–
12/08/15	152	5.19	N45 L38 M10 E7	266	–	–	–	–	–

conj, conjugated bilirubin; DLC, differential leukocyte counts (% N-neutrophils, L-lymphocytes, M-monocytes, E-eosinophils); Hb, haemoglobin; SAP, serum alkaline phosphatase; TLC, total leukocyte counts; TP, total protein; TSB, total serum bilirubin.

On follow-up, his complete blood count and liver function parameters normalised (Table 1) with resolution of organomegaly.

On follow-up, first line ATT were gradually re-introduced one by one but he again had a hypersensitivity reaction to pyrazinamide, so this was replaced by levofloxacin. Dexamethasone doses were gradually tapered off. At the 12-week follow-up, he was asymptomatic with chest radiography showing marked diminution in the size of his mediastinal lesion (Figure 1c) and a negative repeat DCT.

Discussion

AIHA represents a group of disorders where auto-antibodies produced against RBC antigens leads to haemolysis. ⁴ AIHA can be primary or secondary to different disease conditions. Secondary cases account for more than half of the patients with post-infectious forms contributing approximately 10% of cases. ⁴ The management of AIHA involves supportive care and corticosteroid therapy which forms the mainstay of treatment. Splenectomy and Rituximab are options for refractory cases. AIHA has been reported in association with TB in 17 cases (14 adult and three paediatric cases). Eight cases were treated with ATT alone while six required addition of corticosteroid and one splenectomy. All cases showed a very good response with no relapse reported after cessation of therapy. ³

Secondary HLH may be caused by a virus, especially the Epstein Barr virus (EBV), bacteria, fungi, parasites and mycobacteria. ⁶ TB is an infrequent, yet important, cause of secondary HLH. In a review, ⁵ 2.3% of all cases of secondary HLH were found to be associated with mycobacterial infection. Myco. tuberculosis, myco. leprae and atypical mycobacteria all are known to be associated with HLH. Our review of the literature revealed 54 cases of TB-associated HLH in adults, ⁶ with almost half of the patients having one or more co-morbidities. Overall mortality was found to be 50% and all patients not receiving ATT died. While we could find only six reported cases of TB-associated HLH in children, only one was from India. Half of these were boys with ages ranging from 14 days to 15 years; only one patient had isolated pulmonary TB while the rest all had disseminated infection. They received ATT along with steroids and/or intravenous immunoglobulin and four patients recovered. ⁷ Formal guidelines for evaluating patients with HLH secondary to infection have not been established. The available literature suggests a good response to standard ATT regimen with immunosupressants, mainly steroids, in HLH secondary to TB.^6,7 Cases then found not to be responding should be tried with intravenous immunoglobulins (IVIG) before resorting to HLH 2004 protocol. ⁵

We chose to treat our patient with standard ATT along with dexamethasone given in doses as per the HLH 2004 protocol.

We could find only two cases where coexistence of AIHA and HLH were reported. One was a pregnant woman treated with corticosteroid and termination of pregnancy ⁸ and the other was a middle aged woman with systemic lupus erythematosus treated successfully with corticosteroid, IVIG and Rituximab. ⁹ We could not find any case where both AIHA and HLH secondary to TB was reported in the same patient.

Conclusion

Having both AIHA and HLH associated with TB is very unusual. HLH should be considered in the differential diagnosis of a febrile child with cytopenia and organomegaly. The clinical and laboratory features of HLH may evolve over time and a meticulous search may be necessary. Tropical infection associated with HLH seems to have a better prognosis, and may be managed with appropriate therapy of the triggering infection and corticosteroid without the use of cytotoxic chemotherapy.