Sepsis due to Streptococcus pneumoniae associated with secondary hemophagocytic lymphohistiocytosis in a splenectomized patient for spherocytosis

Abstract Rationale: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome that is characterized by an inappropriate hyperinflammatory immune response – primary, as a consequence of a genetic defect of NK cells and cytotoxic T lymphocytes or – secondary, in the progression of infections, rheumatic or autoimmune diseases, malignancies or metabolic diseases. Patient concerns: We present the case of a secondary HLH due to Streptococcus pneumoniae infection in a splenectomised patient for spherocytosis, a 37-year-old patient who was splenectomised in childhood for spherocytosis, without immuneprophylaxis induced by antipneumococcal vaccine. Outcomes: He developed a severe pneumococcal sepsis associated with secondary HLH, with unfavorable outcome and death. Lessons: To our knowledge, just 2 similar cases had been published in the literature, none in which the secondary HLH was the consequence of an invasive pneumococcal infection in a splenectomized patient for spherocytosis, and the association of splenectomy with HLH is surprizin.


Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome that is characterized by an inappropriate hyper-inflammatory immune responseprimary, as a consequence of a genetic defect of NK cells and cytotoxic T lymphocytes orsecondary, in the progression of infections, rheumatic or autoimmune diseases, malignancies or metabolic diseases. Among HLH-related infections, the most common are the viral infections: Epstein--Barr virus, cytomegalovirus, other herpes viruses, the viruses of hepatitis B and C, etc., followed by bacterial, parasitic, or fungal infections. Association of secondary HLH to Streptococcus pneumoniae infection in a patient splenectomized for spherocytosis has not been described so far.

Case report
We present the case of a male Caucasian patient, aged 37 years, splenectomized for spherocytosis since the age of 4, with no prophylaxis of meningococcal, and pneumococcal infections through vaccination, that was brought to the emergency room for fever, diarrhea, vomiting, rash skin, myalgia, anuria, and marked alteration of his general condition. At the time of admission, on physical examination, the following changes were noticed: facial erythema, purpura on the legs (see Fig. 1), cyanosis of the extremities, jaundice, left basilar crackles, heart rate of 130 beats per minute, blood pressure of 140/100 mm Hg, hepatomegaly, and anuria. The laboratory investigations that were performed revealed the following alterations (at admission and in evolution) that are presented in Table 1.
A cardiac ultrasound was performed and revealed no suggestive images of infectious endocarditis or valvular heart disease. Initially, the chest radiography revealed no changes, but in evolution, it showed bilateral alveolar condensation and left pleural effusion.
The case was interpreted as sepsis due to a multidrug-resistant S pneumoniae associated with consumption coagulopathy (bleeding at venepuncture site and epistaxis), acute liver failure, acute renal failure by myoglobinuria, and HLH. In evolution, acute respiratory failure occurred, for which endotracheal intubation of the patient was performed.
The treatment was started with infusions of macromolecular solutions, hydro-electrolytic rebalancing, packed red blood cells, fresh frozen plasma, and antibioticsinitially, with ultrabroadspectrum antibiotics, meropenem 2 g/day associated with linezolid 2 Â 600 mg/day, thereafter treatment continued with linezolid associated with moxifloxacin 400 mg/day according to antibiogram results, dexamethasone, etoposides 150 mg/m 2 /day, 3 days, anidulafungin, intravenous immunoglobulin, and daily hemodialysis sessions throughout hospitalization. The evolution was unfavorable with coma, Glasgow Coma Scale of 3, and quadriplegia, the occurrence of bronchopneumonia required endotracheal intubation. During hospitalization, the patient was anuric. Patient death occurred on day 15 of hospitalization. Hematoxylin-eosin and immunohistochemically stainings of liver

Author
Our case Dalle et al [45] 1995 Ondruschka et al [46]   Although the diagnosis of HLH was early, the administration of dexamethasone, intravenous immunotherapy, and administration of etoposides have not improved prognosis, the patient's death occurring on the 15th day of hospitalization. Renal insufficiency due to bilateral renal papillary necrosis has been associated with myoglobinuria as a result of septic myositis, demonstrated by high levels of creatine phosphokinase. There have been described situations in which S pneumoniae infections are responsible for the death of patients with primary HLH. [44] Two cases of HLH associated with a pneumococcal infection had been published (see Table 2). HLH association with hereditary spherocytosis is found in association with viral infections, such as parvovirus B19 [47] or Epstein-Barr virus. Moreover, splenectomy is described as a therapeutic method in refractory HLH cases. [48][49][50] 3.1. Informed consent Written informed consent was obtained from the patient's next of kin (from his father) for publication of this case report and any accompanying images. The study was accepted by the Ethics Committee of the hospital and they encouraged publishing the article. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Conclusion
The association of sepsis due to S pneumoniae with secondary HLH in a splenectomized patient for spherocytosis should be taken into consideration in similar cases like ours. To our knowledge, no similar cases had been published in the literature, in which the secondary HLH was the consequence of an invasive pneumococcal infection in a splenectomized patient for spherocytosis, and the association of splenectomy with HLH is surprizing. Other similar observations are necessary in the future.