Hemophagocytic lymphohistiocytosis (HLH) is a syn drome of exces sive and maladaptive infl am ma tion. Primary HLH is most fre quently encoun tered in young chil dren, and, with out timely rec og ni tion and ther apy, can lead to multiorgan fail ure and death. It is most often diag nosed using the HLH- 2004 cri te ria and by iden ti fy ing path o log i cal muta tions. However, the HLH- 2004 cri te ria are not spe cifi c for HLH, and patients can eas ily ful fi ll these diag nos tic cri te ria in other proinflammatory states in which HLH-therapy would not be indicated, including hematologic malignancies, infections, and rheumatologic dis ease. Therefore, great care must be taken to ensure that the spe cifi c dis ease asso ci ated with fea tures of HLH is accu rately rec og nized, as con se quences of improper treat ment can be cat a strophic. We pro pose a diag nos tic path way for patients for whom HLH is on the dif fer en tial (visual abstract). Importantly, in sit u a tions in which the ini tial diag nos tic workup is equiv o cal or unrevealing, reevaluation for occult malig nancy, infec tion, or rheumatologic disease would be prudent, as occult presentations may be missed on primary evaluation. Temporizing medications can be used in crit i cally ill patients while awaiting sec ond ary eval u a tion. By using this frame work, cli ni cians will be able to more reli ably dis cern pri mary HLH from other pro- infl am ma tory states and thus pro vide timely, appro pri ate dis ease- specific therapy.
