In paroxysmal nocturnal hemoglobinuria (PNH), the absence of the glycosyl phosphatidylinositol (GPI)-anchored proteins induces hemolytic anemia, thrombosis and smooth muscle dystonias. PNH is a chronic condition and its treatment includes 1) allogeneic bone marrow transplantation, 2) eculizumab, a humanized monoclonal antibody against the terminal complement protein C5 [7, 8] and 3) supportive care such as transfusion, iron and folic acid supplementation and prophylactic anti-coagulation. However, sometimes patients have acute attacks. Corticosteroid can alleviate a hemolytic paroxysm and improve hemoglobin levels in about 60% of PNH patients. But a long-term continuous administration of high dose corticosteroid is troubled with its toxicity . Due to immunosuppression of corticosteroid, CDC recommends prophylactic anti-TB medication in patients with more than 15 mg/day prednisone over 1 month .
Worldwide, for the elimination of TB, identification and treatment of latent tuberculosis infection (LTBI) are essential [9–12]. LTBI is a condition in which a person is infected with dormant Mycobacterium tuberculosis organisms, but does not currently have active TB disease . According to ATS for TB, following patients with LTBI should be considered for anti-TB medication; HIV infection, organ transplantation related to immune- suppressant therapy, recent TB infection within 2 years, TNF inhibitors. In cellular immunity of TB, lymphocyte is a major part of immune activity [4, 14]. In patients with hematologic disease, T-cell immunodeficiency was induced by hematologic disease itself, chemotherapy, corticosteroid and other underlying diseases . Hahn et al. reported that the prevalence of active TB in hematologic disorders was 0.8% in total, with 21.4% in myelofibrosis, 20% in PNH and 7.9% in myelodysplastic syndrome in Korea. Although in this report, the prevalence of TB in the hematologic disorder was not significantly different compared with control group, the incidence of TB in PNH was very high . There are many controversies in the incidence of TB in immunosuppressed patients. In clinical practice, considering risk and an incidence, the diagnosis and treatment of LTBI should be determined. However, there is a problem in determination of prophylactic anti-TB medication, that is to say limitation of the diagnostic methods for LTBI in immunosuppressed patients.
American Thoracic Society (ATS) proposed targeted tuberculin skin test (TST) as a diagnostic tool for LTBI in high-risk group and in the U.S. diagnostic guidelines of 2000, an immunologic test was described. QunatiFERON-TB Gold (QFT-G) is an interferon-gamma releasing assay (IGRA) and it was approved by the FDA for the diagnosis of TB in 2005 and replaced TST [4, 17]. In Korea with high prevalence of TB and high false positivity of TST due to BCG vaccination, IGRA replace TST. But IGRA has a limitation in differentiation of active TB from LTBI, and when patient was treated with LTBI or active TB in the past, it can’t determine whether or not new infection is developed. Also in patients with immunosuppression and complete recovery from TB at the same time, there is no guideline.
On the other hand, miliary TB accounts for about 1% of all cases of TB and the mortality related to miliary TB is about 25–30% in adults . Miliary TB may infect any number of organs, including the lungs, liver and spleen. Hematologic abnormalities are frequently described and pancytopenia is profound in hematolgic diseases. In malignant diseases, the incidence of miliary TB is about 3% and it rarely reported in hematologic diseases [18, 19].
In our patient, before the administration of immunosuppressive drugs for control of acute hemolysis, we wanted to perform the test for detection of LTBI according to CDC for TB. However, since our patient did not have clinical and radiological evidence of active TB and he was completely cured TB in the past, he was not indicated to test and prophylactic anti-TB medication. In addition, because anti-TB medication frequently induces hepatic dysfunction, poor oral intake, nausea and vomiting, the administration prophylactic anti-TB medication is very troubled in seriously ill patient out of guideline. However, he contracted miliary TB and we were in confusion. The treatment for TB was not easy because he complained of nausea, vomiting and poor oral intake and his laboratory findings showed severe pancytopenia and liver dysfunction. Meanwhile, fever is the sign that needs differential diagnosis. He had fever at diagnosis of PNH due to hemolysis and he was checked chest X-ray regularly (weekly). But, miliary TB was developed in one week. So in patients with fever and immunosuppressive drugs, inspection and chest X-ray at intervals of 2 or 3 days are needed.
In conclusion, except some advanced country, TB is endemic disease in worldwide yet. Also, there are differences of TB prevalence between the subgroups of hematologic diseases. So we emphasize the need to investigate multicentral TB prevalence and to make an urgent decision of details of the guidelines for anti-TB medication in patients with subgroups of hematologic diseases including PNH.