Hemophagocytic lymphohistiocytosis (HLH), or "hemophagocytic syndrome," is an uncommon inflammatory disorder characterized by the presence of fever and pancytopenia, often in association with an underlying infection, autoimmune disorder, or malignancy. We present a case of HLH in a 16 year-old girl who had been on immunosuppressive therapy with prednisone and mycophenolate for treatment of systemic lupus erythematosus (SLE)-associated nephritis.
A sixteen-year old girl with SLE was hospitalized for evaluation of fever of unknown origin. She was in her usual state of health until 3 weeks before hospitalization, when she began to have daily fevers up to 39°C associated with fatigue and a dry persistent cough. Her medical history was significant for lupus nephritis diagnosed at age 13. Renal biopsy showed World Health Organization class III nephritis without chronicity. She underwent treatment with pulse steroids and cyclophosphamide for 2 years. Her nephritis was subsequently well controlled until 6 months before admission, when she experienced an exacerbation requiring pulse steroids and the addition of mycophenylate (1500 mg twice daily). This regimen was associated with a rapid resolution of her symptoms, and her prednisone was tapered to 5 mg/d. Her only other medication was trimethoprim/sulfamethoxazole 3 times per week for prophylaxis against Pneumocystis infection.
On physical examination, the patient appeared pale and fatigued. Her temperature was 40.4°C; pulse, 110 beats per min; respiratory rate, 32 per min; and blood pressure, 112/68 mm Hg. She had decreased breath sounds at the left base. There were no rales or wheezes. Her heart sounds were normal. Her abdomen was soft and nontender. The liver and spleen were palpable 2 cm below the costal margins. The remainder of her physical examination was normal.
A chest radiograph demonstrated bilateral densities at the bases, with a small pleural effusion on the left side. Her laboratory evaluation showed a white blood cell count of 3100 cells/μL with 60% neutrophils, 12% bands, 20% lymphocytes, and 8% monocytes; hemoglobin level, 10.8 g/dL; and platelet count, 63,000/μL. The alanine aminotransferase level was 191 U/L; aspartate aminotransferase, 293 U/L; total bilirubin, 3.2 mg/dL; creatinine, 0.8 mg/dL; C3 level, 66 mg/dL; fibrinogen, 340 mg/dL; ferritin, 1800 μg/L; and triglycerides, 218 mg/dL. Standard blood cultures, sputum cultures, viral cultures, and cytomegalovirus antigen were negative. Serologic test results for acute hepatitis A, B, and C, Epstein-Barr virus, HIV, Toxoplasma, and parvovirus B19 were negative. Bone marrow stains showed erythrophagocytosis and a moderate number of histiocytes (Fig. 1), but no pathogens. Bronchoscopy revealed no gross abnormalities of the respiratory tract; however, fungal cultures obtained by bronchoalveolar lavage were positive for Histoplasma capsulatum. Fungal cultures of the blood and bone marrow also grew H. capsulatum. Antifungal treatment was initiated, and mycophenolate was discontinued.
Within days of initiating treatment with liposomal amphotericin B (5 mg/kg/d), defervescence occurred. Her symptoms of dyspnea improved during the following week. After 7 days of amphotericin treatment, she was switched to itraconazole (400 mg/d). Her pancytopenia resolved over a 2-week period. At 9-month follow-up, she remained well. Management of her lupus-associated nephritis at follow-up included prednisone and cyclosporine. Itraconazole therapy is ongoing.
Hemophagocytic lymphohistiocytosis, also commonly referred to as hemophagocytic syndrome, is a nonmalignant proliferative disorder that affects antigen-processing macrophages and results in uncontrolled hemophagocytosis with up-regulation of inflammatory cytokines, including tumor necrosis factor-1α and interleukins-1 and 6. Primary HLH comprises a group of genetic disorders, including mutations in the gene encoding perforin, and immune deficiency syndromes such as X-linked lymphoproliferative disorder and Chediak-Higashi syndrome. Acquired or secondary HLH is a reactive disorder causing robust immune activation resulting from infection, autoimmune diseases (especially SLE), malignancy, or medication.
The formal diagnostic criteria for HLH are fulfilled if there is molecular confirmation of the perforin gene mutation or if 5 of the following features of the disease are identified: fever, splenomegaly, cytopenias involving 2 or more cell lines, hypertriglyceridemia or hypofibrinogenemia, hyperferritinemia, increased interleukin-2 receptor (sCD25), reduced or absent natural killer cell activity, and hemophagocytosis in bone marrow, cerebrospinal fluid, or lymph nodes (Treatment Protocol of the 2nd International HLH Study, 2004, available at www.histio.org/society/HLH/henter1.shtml). There is increasing evidence that some patients do not meet all of these criteria and that many patients do so only late in the course of the disease.
Viruses are the most common group of infectious agents to be implicated as triggers of HLH, with the Epstein-Barr virus being the single most common cause.1 In a recent review of 19 US children with HLH,2 an infectious trigger was documented in 42%. Similarly, 61% of 18 Taiwanese children with HLH had a documented infectious trigger.3 Viruses accounted for all of the documented infectious triggers in both of these series.
Upon initial evaluation of our patient, we considered that the cause of the HLH could be an exacerbation of her SLE. We began to doubt this possibility because her renal function remained stable and her C3 levels remained in the reference range. An aggressive evaluation for an alternate infectious trigger led to the diagnosis of disseminated histoplasmosis, and treatment of the infection was initiated. The rapid resolution of our patient's HLH coincident with the initiation of antifungal therapy supports the contention that the HLH was indeed triggered by the Histoplasma infection.
Many of the clinical signs and symptoms that are associated with HLH are also commonly seen in patients who are ultimately diagnosed with disseminated histoplasmosis. Patients with disseminated histoplasmosis, such as the case we present here, may demonstrate classic bone marrow findings of HLH, whereas others may have normal or very subtle bone marrow abnormalities. One possibility is that disseminated histoplasmosis infection causes HLH more frequently than clinically appreciated.
To date, fungal infections that elicit HLH in children are described only as single case reports, and thus, the precise distribution and spectrum of the fungi associated with this disorder are largely unknown. Existing reports include cases of disseminated aspergillosis in an HIV-infected child,4 cryptococcal meningitis,5 and disseminated Trichosporon beigelii (now Trichosporon asahii) infection in a newborn.6 The association between disseminated histoplasmosis and HLH has been described in adult patients with AIDS,7 an adult heart transplant patient,8 and in a 6-year-old boy with chronic mucocutaneous candidiasis.9
It is important to consider the infectious causes of HLH in patients with SLE, particularly those who require treatment with aggressive immunosuppressive regimens. A high level of vigilance and a comprehensive search for a potential opportunistic infection are particularly important in this patient population because the treatment of SLE-associated HLH (in the absence of infection) centers on increasing immunosuppressive therapy, whereas identification and treatment of an infectious trigger will result in rapid resolution of HLH-associated signs and symptoms.
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