## 3 Discussion  
HLH is a rare, life-threatening immunological disorder. Due to its rapid onset, menacing symptoms and potential end organ damage, it requires prompt diagnosis and treatment. Our patient fulfilled 6 out of 8 diagnostic criteria for HLH according to the HLH-2004 protocol, and thus his clinical presentation was deemed highly suspicious for HLH. Moreover, he presented with hyperferritinemia and a low percentage of glycosylated ferritin, which has been proven to be a highly specific diagnostic marker and a poor prognostic marker for HLH [10,11]. While the diagnostic workup pointed towards HLH early on during the patient's hospital stay, the search for a triggering factor proved to be complicated. Primary HLH was ruled out mainly because of the patient's age. The patient was affected by a HCL which has rarely reported to be the triggering factor for sHLH, but, on the other hand, it is widely known as a strong immunosuppressive malignancy [12]. This, combined with the prolonged steroid therapy and the unknown consequences of a severe SARS-CoV-2 infection, led the diagnostic path towards a secondary infectious cause of HLH. _Mycobacterium tuberculosis_ infection is a known rare trigger of sHLH [13] in immunocompromised patients. The man's occupation, his prolonged steroid therapy and HCL were all significant risk factors for MTB infection, which developed atypically without  
Figure 1: Ferritin (blue) total bilirubin (green) and neutrophil count (orange) trend during the patient’s hospital stay (days after hospitalization). The black arrows indicate the two time points at which Etoposide (day 9) and antitubercolar treatments (day 29) were administered. ANC: Absolute Neutrophil Count; VP16: Etoposide. pulmonary lesions and without detection of MTB-DNA on bronchial wash fluids. The only evidence of MTB infection found has been positive blood cultures, as lymph-node biopsy could not be performed because of the involved lymph-node anatomical location and the patient's general conditions. As a triggering factor was not initially found and the patient's conditions were rapidly worsening, we started chemotherapy according to the HLH-2004 protocol, with high dose dexamethasone and etoposide, obtaining a partial and limited response, as shown by the mild decrease of liver function enzymes and bilirubin right after the first administration of etoposide (Figure 1). While this line of therapy proved to be ineffective, as the patient had to be admitted to the ICU shortly after, it may have given us the necessary time to detect MTC on blood cultures and subsequently start with the appropriate treatment. Given the important role played by HCL-derived immunosuppression in this patient's presentation, we decided to treat the underlying haematological disorder once his clinical condition improved. Considering the important monocytopenia and neutropenia, and the consequential higher risk for opportunistic infections, we preferred to treat the disease with Vemurafenib rather than purine analog 2 CDA (Cladribine), as treatment with Cladribine is associated with higher toxicity towards the immune system, especially regarding the T cell compartment [14; 15]. The case we presented points out the role of MTC infections in immunocompromised patients as a triggering factor for sHLH, even in the absence of typical pulmonary lesions or a history suggestive of primary MTC infection. MTB infection in our patient was recent, as a QuantiFeron-TB Gold test was negative during his first hospitalization, and it is unknown whether long-COVID complications and/or immunosuppressive triggered by HCL might have favored the development of military MTC disease. Moreover, is that HLH-directed chemotherapy based on high dose corticosteroids and etoposide, other than being the first appropriate treatment when a triggering factor cannot be found, can give the clinicians time to identify rare and potentially treatable underlying disease.