Clinical features and treatment outcomes of opportunistic infections among human T-lymphotrophic virus type 1 (HTLV-1) carriers and patients with adult T-cell leukemia-lymphoma (ATL) at a single institution from 2006 to 2016

Abstract

As opportunistic infections among human T-lymphotrophic virus type 1 (HTLV-1) carriers and patients with adult T-cell leukemia/lymphoma (ATL) pose a serious problem, it is necessary to clarify their clinical characteristics and outcomes in these patients. We retrospectively analyzed the clinical features and outcomes of opportunistic infections in 127 HTLV-1 carriers and 153 ATL patients between 2006 and 2016. The cumulative incidence rates of opportunistic infections among HTLV-1 carriers and ATL patients were 1.5% (2/127) and 6.5% (10/153), respectively. The etiology of opportunistic infections was as follows: fungal infections (3 cases), pneumocystis pneumonia, and cytomegalovirus (CMV) infections. Even after aggressive treatment, the prognosis of opportunistic infections was poor (50% of overall survival at 28 days). Regarding prognostic factors affecting the OS of opportunistic infections, higher SOFA scores (especially the respiratory subscore) and higher LDH values were identified by univariate analysis. Moreover, 3 out of 6 patients achieved spontaneous remission of ATL as the short-term outcome after the development of opportunistic infection. However, 5 out of 6 surviving patients exhibited ATL progression or relapse after a median of 194 days (133-226) after contracting an opportunistic infection as the long-term outcome of ATL. In conclusion, opportunistic infections should be carefully followed among HTLV-1 carriers and ATL patients because of their aggressive clinical course and poor outcomes. Furthermore, early diagnosis and subsequent prompt treatment are necessary in clinical practice.

Keywords: HTLV-1 carrier; adult T-cell leukemia/lymphoma; opportunistic infection; progression of ATL; spontaneous remission of ATL.

Fig. 1A

Clinical course of case 11. Age 54 years, chronic-type ATL, pneumocystis pneumonia → improvement → the development of acute-type ATL. A 54-year-old male was followed for chronic-type ATL with the CD3⁺CD4⁺CD25⁺CD5⁺CD7⁺ phenotype on FCM analysis and a monoclonal band on Southern blot analysis. The patient presented with acute progressive respiratory failure. Laboratory findings were as follows: WBC 32550/μL (60%), LDH 500 IU/ml, sIL2R 14500 IU/ml, CRP 2 mg/dl, β-D-glucan: 353.7 pg/mL, Aspergillus Ag(-), and CMV C7 HRP(-). Furthermore, CT showed bilateral interstitial pneumonia sparing the normal lung field under the pleural membrane. BAL analysis revealed a foamy population after May–Giemsa staining, Papanicolaou staining, and Grocott staining. Furthermore, Pneumocystis jiroveci was confirmed by PCR analysis. These findings led to the final diagnosis of Pneumocystis pneumonia. Subsequent ST treatment and mPSL pulse therapy led to the cure of Pneumocystis pneumonia. During the treatment of Pneumocystis pneumonia, the status of ATL was PR. However, chronic-type ATL progressed to acute-type ATL on day 153. Subsequent chemotherapy including mLSG 15 and allo-HSCT led to CR of ATL on day 631.

Fig. 1B

Clinical course of case 6. Age 56 years, acute-type ATL, CMV pneumonia → improvement → ATL relapse. A 56-year-old female was diagnosed with acute-type ATL and treated using the mLSG 15 regimen. However, the disease status of ATL was PD after mLSG 15 therapy. During chemotherapy, the patient developed acute progressive respiratory failure due to opportunistic infection. Subsequent CT revealed bilateral interstitial pneumonia. Based on the positive findings of CMV C7-HRP in PB and CMV PCR in BALF, CMV pneumonia was diagnosed. Subsequent DHPG therapy and mPSL pulse therapy cured CMV pneumonia within 52 days. During the treatment of CMV pneumonia, the disease status of ATL was CR, but she developed isolated CNS relapse on day 213. Subsequent RTx did not affect the CNS lesions of ATL at 240 days.

Fig. 2

The changes in parameters related to opportunistic infection after treatment. We compared the changes of parameters related to infection in immunocompromised patients after treatment in 12 cases of opportunistic infection. The values of β-D-glucan and CMV C7-HRP decreased after treatment of opportunistic infections (Pneumocystis pneumonia and CMV pneumonia, respectively). The SOFA scores decreased in survivors and deteriorated in non-survivors.

Fig. 3

The changes in parameters related to ATL after treatment. We examined the changes in parameters related to ATL after treatment. The values of WBC, Ab-ly, LDH, Ca, and sIL-2R decreased after treatment of opportunistic infection.

Fig. 4

Treatment outcomes of opportunistic infection among HTLV-1 carriers and ATL patients. We investigated treatment outcomes of 12 cases of opportunistic infection among ATL patients and HTLV-1 carriers. The prognosis was poor: OS of 28 days and OS rate of 50% (6/12). Among 6 survivors, 5 presented with ATL PD (3 patients) and relapse of ATL (2 patients) at a median of 194 days (range 133–226). Thus, the median OS was 121 days and OS rate was 16.7% (2/12).

Fig. 5

Clinical presentation of a spontaneous-remission case before and after treatment according to FCM analysis, Southern blotting, and CTL analysis. Presented are the CT findings, FCM analysis, southern blot analysis, and CTL analysis by a tetramer assay in a representative case of spontaneous remission of ATL (case 6) after treatment of opportunistic infection (A-D). CT findings after treatment of CMV pneumonia showed the improvement of CMV pneumonia (A-a and A-b). FCM findings after treatment of opportunistic infection demonstrated the improvement of CMV pneumonia (B-a and B-b). Southern blot analysis after treatment of opportunistic infection showed the absence of HTLV-1 clonality in PB (C-a and C-b). Thus, CR was achieved because of the disappearance of ATL cells on smears of PB, FCM analysis, and Southern blot analysis after CMV pneumonia (A–D). Furthermore, case 6 had 47% CD8⁺ T cells and 11% NK cells according to FCM analysis of PB. In the HLA-A24 FCM tetramer assay, there were 0.03% HLA-24–restricted HTLV-1–specific CTLs and 0.1% HLA-24–restricted CMV-specific CTLs (D). Thus, CTL analysis by HLA 24 restrictive FCM analysis after treatment of opportunistic infection confirmed the presence of CMV-specific CTLs and HTLV-1-specific CTLs.