Hot in the tropics
© 2017 Society of Hospital Medicine
PCR for HIV would be positive at a high level in acute HIV. The skin biopsy is not characteristic of Sweet syndrome, which typically shows neutrophilic infiltrate without leukocytoclastic vasculitis, or of syphilis, which typically shows a plasma cell infiltrate.
The patient’s erythematous oropharynx may indicate recent streptococcal pharyngitis. The fevers, elevated ASO titer, and CRP level are consistent with acute rheumatic fever, but arthritis, carditis, and neurologic manifestations are lacking. Erythema marginatum manifests on the trunk and limbs as macules or papules with central clearing as the lesions spread outward—and differs from the patient’s rash, which is firm and restricted to the abdominal wall.
Fevers persisted through hospital day 7. The WBC count was 1100/μL (75.7% neutrophils, 22.5% lymphocytes), hemoglobin was 10.3 g/dL, and platelet count was 52,000/μL. Additional laboratory test results included ALP, 234 U/L; ALT, 250 U/L; AST, 459 U/L; lactate dehydrogenase, 2303 U/L (reference range, 222-454 U/L); and ferritin, 14,964 ng/mL (reference range, 47-452 ng/mL).
The duration of illness and negative diagnostic tests for infections increases suspicion for a noninfectious illness. Conditions commonly associated with marked hyperferritinemia include adult-onset Still disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). Of the 9 AOSD diagnostic (Yamaguchi) criteria, 5 are met in this case: fever, rash, sore throat, abnormal liver function tests, and negative rheumatologic tests. However, the patient lacks arthritis, leukocytosis, lymphadenopathy, and hepatosplenomegaly. Except for the elevated ferritin, the AOSD criteria overlap substantially with the criteria for acute rheumatic fever, and still require that infections be adequately excluded. HLH, a state of abnormal immune activation with resultant organ dysfunction, can be a primary disorder, but in adults more often is secondary to underlying infectious, autoimmune, or malignant (often lymphoma) conditions. Elevated ferritin, cytopenias, elevated ALT and AST, elevated CRP and erythrocyte sedimentation rate, and elevated lactate dehydrogenase are consistent with HLH. The HLH diagnosis can be more firmly established with the more specific findings of hypertriglyceridemia, hypofibrinogenemia, and elevated soluble CD25 level. The histopathologic finding of hemophagocytosis in the bone marrow, lymph nodes, or liver may further support the diagnosis of HLH.
Rash and fevers persisted. Hepatitis A, hepatitis C, Rickettsia IgG, Burkholderia pseudomallei (the causative organism of melioidosis), and Leptospira serologies, as well as PCR for herpes simplex virus and parvovirus, were all negative. Hepatitis B viral load was 962 IU/mL (2.98 log), hepatitis B envelope antigen was negative, and hepatitis B envelope antibody was positive. Orientia tsutsugamushi (organism responsible for scrub typhus) IgG titer was elevated at 1:128. Antiliver kidney microsomal antibodies and antineutrophil cytoplasmic antibodies were negative. Fibrinogen level was 0.69 g/L (reference range, 1.8-4.8 g/L), and beta-2 microglobulin level was 5078 ng/mL (reference range, 878-2000 ng/mL). Bone marrow biopsy results showed hypocellular marrow with suppressed myelopoiesis, few atypical lymphoid cells, and few hemophagocytes. Flow cytometry was negative for clonal B lymphocytes and aberrant expression of T lymphocytes. Bone marrow myobacterial PCR and fungal cultures were negative.
The patient’s chronic HBV infection is unlikely to be related to his presentation given his low viral load and absence of signs of hepatic dysfunction. Excluding rickettsial disease requires paired acute and convalescent serologies. O tsutsugamushi, the causative agent of the rickettsial disease scrub typhus, is endemic in Malaysia; thus, his positive O tsutsugamushi IgG may indicate past exposure. His fevers, myalgias, truncal rash, and hepatitis are consistent with scrub typhus, but he lacks the characteristic severe headache and generalized lymphadenopathy. Although eschar formation with evolution of a papular rash is common in scrub typhus, it is often absent in the variant found in Southeast Asia. Although elevated β2 microglobulin level is used as a prognostic marker in multiple myeloma and Waldenström macroglobulinemia, it can be elevated in many immune-active states. The patient likely has HLH, which is supported by the hemophagocytosis seen on bone marrow biopsy, and the hypofibrinogenemia. Potential HLH triggers include O tsutsugamushi infection or recent streptococcal pharyngitis.
A deep-punch skin biopsy of the anterior abdominal wall skin lesion was performed because of the absence of subcutaneous fat in the first biopsy specimen. The latest biopsy results showed irregular interstitial expansion of medium-size lymphocytes in a lobular panniculated pattern. The lymphocytes contained enlarged, irregularly contoured nucleoli and were positive for T-cell markers CD2 and CD3 with reduction in CD5 expression. The lymphomatous cells were of CD8+ with uniform expression of activated cytotoxic granule protein granzyme B and were positive for T-cell hemireceptor β.
Positron emission tomography (PET) CT, obtained for staging purposes, showed multiple hypermetabolic subcutaneous and cutaneous lesions over the torso and upper and lower limbs—compatible with lymphomatous infiltrates (Figure 2). Examination, pathology, and imaging findings suggested a rare neoplasm: subcutaneous panniculitis-like T-cell lymphoma (SPTCL). SPTCL was confirmed by T-cell receptor gene rearrangements studies.
HLH was diagnosed on the basis of the fevers, cytopenias, hypofibrinogenemia, elevated ferritin level, and evidence of hemophagocytosis. SPTCL was suspected as the HLH trigger.
The patient was treated with cyclophosphamide, hydroxydoxorubicin, vincristine, and prednisone. While on this regimen, he developed new skin lesions, and his ferritin level was persistently elevated. He was switched to romidepsin, a histone deacetylase inhibitor that specifically targets cutaneous T-cell lymphoma, but the lesions continued to progress. The patient then was treated with gemcitabine, dexamethasone, and cisplatin, and the rashes resolved. The most recent PET-CT showed nearly complete resolution of the subcutaneous lesions.
