Under-Recognition of Hemophagocytic Lymphohistiocytosis in United States' Rural, Non-Teaching Hospitals

Introduction: Hemophagocytic Lymphohistiocytosis (HLH) is a rare syndrome characterized by excessive immune activation with an aggressive disease course and life-threatening consequences. Secondary HLH has been found to be triggered by various malignancies among its etiologies, most commonly being leukemia’s and lymphoid malignancies. Rapid diagnosis and prompt initiation of treatment are paramount for survival in HLH. However, the rarity of this syndrome and the complex clinical picture often prove to be a barrier to diagnosis.

Methods: We identified all adult hospitalizations with HLH from the United States Nationwide Inpatient Sample (NIS) database from 2009-2011 using International Classification of Diseases-9th revision, Clinical Modification (ICD-9-CM) codes 288.4. Only those cases undergoing bone marrow aspiration/biopsy were selected to improve diagnostic accuracy. We assessed the distribution of these diagnoses by hospital teaching status (teaching versus non teaching) and location (rural versus urban). Statistical analysis was done using STATA 13.0 (StataCorp LP, College Station, TX). All p-values were two sided and the level of significance was 0.05.

Results: A total of 276 hospitalizations with HLH were identified, out of which 44 (16%) had a concomitant diagnosis of a malignancy. The median age at diagnosis was 42 years (range 18-89 years) and 43% (n=114) of the cases were females. Out of a total 23,634,793 hospitalizations during this time period, 12,532,948 (53%) belonged to non-teaching hospitals and 11,101,845 (47%) belonged to teaching hospitals. Similarly, a total of 2,867,148 (12%) belonged to rural hospitals and 20,767,645 (88%) belonged to urban hospitals. Among HLH cases, 90% (n=248) belonged to teaching hospitals and 99% (n=273) belonged to urban hospitals. Chi-square test showed that cases with HLH were more likely to be diagnosed in a teaching hospital (p value <0.01) and urban hospitals (p-value <0.01). Of the 44 cases with an underlying malignancy, 38 (86.3%) were associated with a hematological malignancy and 5 (11.3%) with a solid tumor. The tumor type was not specified for one patient. The in-hospital mortality for HLH with and without underlying malignancy was 29.56% (n=13) and 14.2 % (n=33) respectively (p-value 0.01). Inpatient mortality was 29% (n=11) for patients with an associated hematological malignancy and 40% (n=2) for those with associated solid tumor. Comparison of outcomes between rural and urban hospitals and teaching and non-teaching hospitals was not feasible due to the skewing of case distributions.

Conclusions:

HLH secondary to an underlying malignancy is associated with a higher mortality rate as compared to HLH without an underlying malignancy. Over 90% of the cases of HLH were diagnosed in an urban or teaching hospital setting. Given the complexities in diagnosing HLH, we think that the disease may be underreported in the rural and non-teaching setting. As secondary, malignancy associated HLH carries a poor prognosis, better recognition of HLH is needed in order to aid physicians’ diagnosis and treatment of this syndrome in all hospital settings.