Comoli P.

Contardi G.

Fronti E.

MINOLI, LORENZO

Rubert L.

Seminari E.

Zecca M.

English

Archivio Istituzionale della Ricerca - Università degli Studi di Pavia

INT J TUBERC LUNG DIS 18(2):248–252© 2014 The UnionCORRESPONDENCECorrespondenceTuberculosis-induced haemophagocytic syndrome in a patient on haemodialysis treated with anti-thymocyte globulinWe report a case of haemophagocytic syndrome as-sociated with tuberculosis successfully treated with anti-thymocyte globulin (ATG) and steroids.In October 2011, a 22-year-old man with a history of end-stage renal disease was admitted to his referral centre with interstitial pneumonia. Despite antibiotic treatment he remained febrile. Bone marrow biopsy showed histiocytosis with haemophagocytosis; the patient was transferred to our hospital to start treat-ment for haemophagocytic syndrome. Thoracic computed tomography (CT) showed mul-tiple peribronchial panlobular infi ltrates with intra-lobular interstial tree-in-bud thickness and mediastinal lymphadenopathy without caseous lesions. Ziehl-Neelsen-positive bacteria, subsequently identifi ed as Mycobacterium tuberculosis by culture, were detected in bronchoalveolar lavage (BAL) fl uid. Bone marrow biopsy showed several granulomas surrounded by epi-thelioid histiocytes containing acid-fast bacilli. Anti-tuberculosis treatment was started with isoniazid, rifampicin and ethambutol. He had persistent anaemia with normal erythropoietin levels, symptomatic throm-bocytopaenia, leucopaenia and hyperferritinaemia (33 324 ng/ml). The patient received dexamethasone (10 mg/m2/day) and intravenous immunoglobulin, with no signifi cant clinical or haematological response; cyclosporine was unsuccessful due to pharmacokinetic interaction with rifampicin. Three weeks after the start of anti-tuberculosis treat-ment, the patient developed high fever with increased C-reactive protein, procalcitonin and ferritin levels, fol-lowed by acute respiratory failure requiring continu-ous positive airway pressure the following day. Blood culture yielded negative results, and he did not re-spond to empirical antibiotic treatment. Thoracic CT revealed interstitial thickening (Figure); BAL showed haemorrhagic alveolitis. This clinical picture was in-terpreted as a complication of haemophagocytosis. Etoposide was not prescribed because of the risk of secondary aplasia. It was decided to treat the patient with a course of ATG (Thymoglobulin®, Genzyme™, Cambridge, MA, USA) 3.75 mg/kg/day for 5 days in association with methylprednisolone 30 mg tid. The patient showed improvement within a few days, and 3 months after diagnosis he was dismissed from hos-pital following a therapeutic programme of slow ste-roid tapering and continued anti-tuberculosis treat-ment. Eighteen months after diagnosis the patient was cured of tuberculosis and haemophagocytic syn-drome; he is still receiving a low dose of steroids (prednisone 10 mg e very other day).Haemophagocytic syndrome is a serious histiocytic disorder characterised by an uncontrolled, dysfunc-tional immune response leading to activation and pro-liferation of macrophages.1 Secondary haemophago-cytic syndrome has frequently been associated with intracellular pathogens that typically induce type 1 T-helper immune responses.2 The triggering agents in haemophagocytic syndrome are usually viruses of the herpes group, in particular Epstein-Barr and cytomegalovirus, or M. tuberculosis.2 Haemophago-cytic syndrome mortality due to tuberculosis is ap-proximately 50%.2 Immunochemotherapy consists of combination therapy with etoposide, dexamethasone and cyclosporine.1 In the present case the use of con-ventional therapy did not seem feasible due to the high risk of liver toxicity and bone marrow aplasia. We therefore decided to use ATG, which had been used successfully in patients with familial haemophagocytic lymphohistiocytosis, yielding 73% complete responses3 and in two cases secondary haemophagocytic syn-drome.4 The rationale for ATG immunotherapy in fa-milial haemophagocytic lymphohistiocytosis is strongly based on the primary role of defective cytolytic T-cells in the pathogenesis of the disease. This is underlined by the observation that anti-T-cell a ntibody therapy can control experimental familial haemophagocytic lymphohistiocytosis in lymphochoriomeningitis virus-infected, perforin-defi cient mice.5 Despite these posi-tive experiences, using ATG in a patient with dissemi-nated tuberculosis is not without risk, as cell-mediated immunity has long been known to play a key role in the control of mycobacterial infections. Figure Computed tomography scan showing interstitial thick-ening concomitant with bronchoalveolar lavage diagnosis of haemorrhagic alveolitis.Correspondence  249Our observation suggests that ATG may be con-sidered for the treatment of haemophagocytic lympho-histiocytosis in cases where standard chemotherapy with etoposide and cyclosporine is contraindicated. Elena Seminari*Giada Contardi*Laura Rubert† Elisa Fronti*Patrizia Comoli† Lorenzo Minoli*Marco Zecca†*Clinica di Malattie Infettive † Oncoematologia pediátricaFondazione IRCCS Policlinico San MatteoPavia, Italye-mail: e.seminari@smatteo.pv.it http://dx.doi.org/10.5588/ijtld.13.0533References1 Trottestam H, Horne A, Aricò M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood 2011; 118: 4577–4584. 2 Rouphael N G, Talati N J, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syn-drome. Lancet Infect Dis 2007; 7: 814–822. 3 Mahlaoui N, Ouachee-Chardin M, de Saint Basile G, et al. I mmunotherapy of familial hemophagocytic lymphohistiocyto-sis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics 2007; 120: e622–e628.4 Coca A, Bundy K W, Marston B, Huggins J, Looney R J. Macro-phage activation syndrome: serological markers and treatment with anti-thymocyte globulin. Clin Immunol 2009; 132: 10–18.5 Jordan M B, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 2004; 104: 735–743.Recurrence of active tuberculosis following resumption of anti-TNF-𝛂 therapy in a patient with Crohn’s disease Tumour necrosis factor (TNF) α is a cytokine impli-cated in the formation and maintenance of tubercu-lous granulomas. As expected, tuberculosis (TB) is a frequent complication associated with anti-TNF-α therapy.1 Despite the frequency of this opportunistic disease, there are still several areas of uncertainty when active TB develops, mainly regarding the re-introduction of anti-TNF-α and the duration of anti-tuberculosis chemotherapy. Current treatment guidelines recommend the dis-continuation of anti-TNF-α therapy when active TB is diagnosed.2 However, there are no guidelines on the safety of reintroduction of anti-TNF-α drugs in these patients, nor on the most appropriate time to reintro-duce treatment. British Thoracic Society guidelines recommend a minimum of 2 months of full chemo-therapy if TB is diagnosed before the initiation of anti-TNF-α therapy and, if the patient develops active TB while on anti-TNF-α drugs, they could be contin-ued if indicated because of the risk of a fl are-up.3There is limited available information on the course of TB after readministration of anti-TNF-α therapy. We report our experience with early introduction of TNF-α antagonists in a patient with uncontrollable Crohn’s disease. A 19-year-old man with Crohn’s disease of 9 years’ duration had been on adalimumab for 2 years when he was diagnosed with pulmonary TB. The isolate was susceptible to all anti-tuberculosis drugs tested. Treatment with anti-TNF-α was discontinued, and he received a four-drug anti-tuberculosis regimen for 2 months, followed by isoniazid and rifampicin for 7 additional months. He achieved complete clinical and radiological recovery. Because of the patient’s uncontrolled Crohn’s disease despite several alterna-tive regimens, adalimumab was reintroduced during the fourth month of anti-tuberculosis chemotherapy.The patient remained asymptomatic for 11 months after completion of anti-tuberculosis treatment and while on adalimumab. After this period, he devel-oped fever and dry cough. A chest X-ray showed sub-pulmonary left pleural effusion without infi ltrates. Polymerase chain reaction and culture of pleural fl uid were positive for Mycobacterium tuberculosis, again susceptible to all drugs. The patient was restarted on four-drug anti-tuberculosis treatment, once again with good clinical response. This is the fi rst report of TB recurrence after suc-cessful treatment following readministration of anti-TNF-α therapy in a patient with Crohn’s disease. Al-though reinfection cannot be ruled out in this case, the short period of time after anti-tuberculosis treat-ment completion and the site of the disease, which often represents reactivation, led us to suspect a new episode of latent tuberculosis. In the literature search, we found three cases of reintroduction of anti-TNF-α therapy after development of active TB, but in all three cases, treatment was reinitiated after completion of anti-tuberculosis treatment.4 The recurrent TB in our patient could have been related to an inade-quate immune response leading to failure to eradi-cate the mycobacteria. Our case suggests that reintro-duction of anti-TNF-α therapy should be delayed until completion of anti-tuberculosis chemotherapy. When TNF-α antagonists need to be resumed before completion of anti-tuberculosis treatment, a more prolonged course than the standard regimen should be considered and, because of the high risk of recur-rence, close and continuous follow-up while on anti-TNF-α therapy is warranted.Mar Masiá*†Maravillas Martínez* Mariana Fe García-Sepulcre‡ Jesús Sáez‡ Félix Gutiérrez*† 

Tuberculosis-induced haemophagocytic syndrome in a patient on haemodialysis treated with anti-thymocyte globulin.

https://iris.unipv.it/bitstream/11571/822836/1/709BB0B8B30433CE14483567685C253689C65C7CE5.pdf

Tuberculosis-induced haemophagocytic syndrome in a patient on haemodialysis treated with anti-thymocyte globulin.

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