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Clin Exp Immunol. Jun 2009; 156(3): 440–445.
PMCID: PMC2691972

Safety and efficacy of treatment using interleukin-2 in a patient with idiopathic CD4+ lymphopenia and Mycobacterium avium-intracellulare

Abstract

We present the case of a 39-year-old white man with a Myobacterium avium-intracellulare pulmonary infection found to have a CD4+ count of 172 cells/mm3 and diagnosed subsequently with idiopathic CD4+ lymphopenia (ICL). After receiving clathromycin for 4 months with minimal improvement, the patient was started on pegylated subcutaneous interleukin (IL)-2 at 600 000 units daily. Later, he received incrementally higher pegylated IL-2 doses until he reached a maintenance dose 3 months later of 11 million units weekly divided into three equal doses. After 5 months of therapy, the patient's chronic cough resolved completely, sputum cultures became negative for Myobacterium avium-intracellulare and the CD4+ T cell count increased to 553 cells/mm3. After 35 months of well-tolerated IL-2 treatments and no recurrence of any opportunistic infections, IL-2 treatment was stopped. CD4+ counts 6 and 9 months after discontinuing IL-2 treatment were 596 and 378 cells/mm3 respectively, and he remains asymptomatic. This report supports IL-2 treatment for ICL-associated opportunistic infections as a safe and potentially efficacious treatment option, especially when combined with more traditional treatment regimens.

Keywords: IL-2 treatment, ICL, lymphopenia, MAI, T cell

Introduction

Idiopathic CD4+ lymphopenia (ICL) is a rare immune defect described first in a series of early 1990s case reports and characterized further by analysis of HIV-seronegative patients in the national AIDS reporting system and blood transfusion safety studies [17]. The Center for Disease Control established a working definition of ICL including the following criteria: (1) CD4+ T lymphopenia (CD4+ cell count < 300 cells/mm3 or CD4+ cell count < 20% of T cells) on more than one occasion; (2) lack of HIV infection; and (3) no immune deficiency, infection or therapy associated with T cell lymphopenia [1]. In most reported cases, ICL patients present with opportunistic infections including: extrapulmonary and pulmonary Mycobacterium avium complex, Pneumocystis jiroveci pneumonia, cryptococcal meningitis, oral candidiasis, disseminated cutaneous Herpes zoster, cerebral toxoplasmosis and numerous other opportunistic infections [16,8]. However, some ICL patients do not have opportunistic infections and are relatively healthy [8,9]. Initial treatment regimens focused upon preventing or eliminating opportunistic infections with antibiotics, not on improving CD4+ cell counts.

Recent studies continue to support the importance of the CD4+ and natural killer (NK) cells in host immunity to Mycobacterium avium[10,11]. In the last 10 years, isolated ICL case reports have suggested that therapy with interleukin (IL)-2 is efficacious in treating Myobacterium avium-intracellulare (MAI), relapsing Herpes zoster, cryptococcal meningitis and nephritis associated with monoclonal immunoglobulin (Ig)G and IgA gammopathies following the failure of more conventional treatment regimens [1215]. We report a case of a patient with ICL with pulmonary MAI treated with IL-2 combined with anti-microbial therapy who demonstrated marked clinical and immunological improvement.

Materials and methods

In December 2003 a 39-year-old man with a history of asthma and chronic bronchitis presented to a local pulmonologist with a 2-year history of increasingly frequent and severe bronchitis episodes. Bronchitis exacerbations occurred eight to 10 times annually, were associated with cough and dyspnoea, and required antibiotics or systemic steroids for improvement. During the same time-period the patient unintentionally lost 7 pounds (6% of total body weight). The patient's significant past medical history included reportedly well-controlled asthma with as-needed albuterol, resolved chronic warts, allergic rhinitis, sinusitis and a diarrhoeal illness 1 month prior to presentation that resolved with metronidazole. His family history was significant for chronic bronchitis of unknown aetiology in his mother and maternal aunt. The physical examination was without observed warts or other significant findings. Spirometry showed mild small airway obstruction with a minimal response to bronchodilator treatment [forced vital capacity 89% predicted, forced expiratory volume in 1 s (FEV1) 88% predicted, bronchodilator increased FEV1 by 9%], and a chest X-ray demonstrated no infiltrates or hyperinflation. Sputum cultures were positive for MAI. He was diagnosed with MAI infection, and treatment with clarithromycin (500 mg twice daily) along with fluticasone and salmeterol (250/50 one puff twice a day) was started in February 2004. Because of his MAI diagnosis, HIV screening tests, T cell subset cell counts and immunoglobin studies were obtained. These studies revealed a negative HIV-1 screening enzyme-linked immunosorbent assay, a T cell lymphopenia with a marked decreased CD4+ T cell count (white blood cell count 6·5 cells/mcl, CD3+ 318 cells/mm3, CD4+ 172 cells/mm3, CD8+ 103 cells/mm3) and normal immunoglobins (IgG total 1038 mg/dl, IgG1 580 mg/dl, IgG2 417 mg/dl, IgG3 52 mg/dl, IgG4 28 mg/dl, IgA 222 mg/dl, IgE 84 mg/dl). Because of his decreased CD4+ count and his MAI diagnosis he was referred to our clinic for further evaluation.

The patient denied intravenous drug use, homosexual relations, blood transfusions or other HIV risk factors. No other opportunistic infections were detected by patient history. A complete blood count revealed a white blood count of 5·9 cells/mcl (neutrophils 4354, lymphocytes 772, monocytes 531, eosinophils 136, basophils 12), haemoglobin 13·9 g/dl, platelet 297 cell/mcl. A concurrent repeat CD4+ count remained low at 247 cells/mm3 (Fig. 1). An extensive investigation for other aetiologies of CD4+ lymphopenia was undertaken, including: HIV-1,2, human T cell lymphotropic virus (HTLV)-1,2 and chest computed tomography. A bone marrow biopsy revealed a hypocellular bone marrow with trilineage haematopoiesis and no morphological evidence of infectious or infiltrative process. Specific immunophenotypic findings of the bone marrow biopsy included: (1) 69% maturing granulocytic elements; (2) 3·3% monocytes; (3) 1·4% erythroid elements; (4) 0·67% CD34(+) progenitor cells; (5) 3·9% small, mature T lymphocytes (CD4 : CD8 = 0·94:1); (6) 0·6% NK cells; (7) 0·54% haematogones; (8) 0·91% small, mature, polytypic B lymphocytes (kappa : lambda = 2·0:1); and (9) 0·12% plasma cells. Chromosome analysis with the G-banding trypsin–Wright method revealed a normal, 46 XY, male karyotype.

Fig. 1
Absolute CD4+ counts before, during and after interleukin (IL)-2 treatment. The IL-2 doses started at 600 000 units/day in May 2004, were titrated to 11 000 000 units/week by July 2004 and stopped in July of 2007. The patient had had recurrent bronchitis ...

Without an identified infectious or malignant cause for the patient's markedly decreased CD4+ count, we next considered rare adult-onset immunodeficiencies. The patient's lack of warts on physical examination, Ig profile, bone marrow biopsy findings and normal neutrophil counts were inconsistent with the warts, hypogammaglobulinaemia, infection and myelokathexis syndrome [16]. A very small number of case reports have described variant partial adenosine deaminase (ADA) deficiency that presents first in adults [17,18]. In these limited case reports the patients had at least one of the following characteristics: (1) relatives with opportunistic infections or immunodeficiencies; (2) histories of severe childhood infections; and (3) severe lymphopenia. Our patient had none of these clinical characteristics, making ADA deficiency an unlikely diagnosis [17,18]. Based on our low clinical suspicion we did not order specific ADA functional or genetic testing.

We also considered purine nucleoside phosphorylase (PNP) deficiency in our differential diagnosis; however, the only case report of adult diagnosis involved a patient who presented concurrently with common variable immunodefiency, a recurrent lymph node granuloma and splenomegaly [19]. Given that our patient did not have a clinical presentation similar to the one published case report or any childhood features of PNP deficiency, we did not pursue specific testing for this disorder.

Finally, radiosensitivity as associated with the overarching syndrome now known as XCIND (X-ray irradiation sensitivity, cancer susceptibility, immunodeficiency, neurological impairment and double-strand breakage repair) has been associated with T cell subset lymphopenias [20]. More specifically, ataxia–telangiectasia and Nijmegen breakage syndrome have been associated with CD4+ lymphopenia [2124]. However, our patient did not have clinical features consistent with any of these syndromes, a personal or family history of malignancy or a karyotypical analysis consistent with chromosomal instability. These facts made XCIND syndrome an unlikely explanation for his CD4+ lymphopenia. Based on the predominance of the CD4+ lymphopenia without another explanation, we diagnosed ICL.

After a discussion of various treatment options, a review of the previous case repots and obtaining informed consent based on the risks and benefits associated with IL-2 treatment, the patient was started on pegylated subcutaneous IL-2 at 600 000 units daily. In May 2004, the time of his first IL-2 dose, his CD4+ count had increased to 365 cells/mm3. Subsequently, he received incrementally higher pegylated IL-2 doses until he reached a maintenance dose 3 months later of 11 million units weekly divided into three doses (Fig. 1).

Results

After 5 months of IL-2 therapy, the patient's chronic cough resolved completely, sputum cultures became negative for MAI and the CD4+ T cell count increased to 553 cells/mm3. Clarithromycin for MAI treatment was discontinued in October 2004. For the next 35 months IL-2 treatments at 11 million units weekly continued, and CD4+ counts generally remained above 350 cells/mm3, excluding two laboratory dates (Fig. 1). During each of these CD4+ nadirs, repeat HIV-1,2 and HTLV-1,2 all remained negative, and the patient missed several doses of IL-2 during these times. In April 2007, after 35 months of IL-2 treatment with no recurrence of any opportunistic infections IL-2 treatment was stopped. When IL-2 treatment was stopped the patient had the following cellular immunological profile: white blood cell count 6·5 cells/mcl, neutrophils 5005 cells/mm3, lymphocytes 1105 cells/mm3, monocytes 195 cells/mm3, eosinophils 195 cells/mm3, CD3+ 697 cells/mm3, CD4+ 470 cells/mm3, CD8+ 225 cells/mm3, CD19+ 103 cells/mm3 and CD16+/56+ 293 cells/mm3.

During the IL-2 treatment period the patient had no reported illnesses, other than two upper respiratory infections with negative acid fast bacteria and bacterial sputum cultures each time. He tolerated the IL-2 with no major side effects other than occasional mild fatigue and influenza-like symptoms, one documented reactive lymph node and transient eosinophilia (maximum 1335 cells/mm3). CD4+ counts 6 and 9 months after discontinuing IL-2 treatment were 596 and 378 cells/mm3 respectively. On examination 9 months after stopping IL-2 he has had no signs or symptoms of other opportunistic infections, no reported or observed warts during the study period and no delayed IL-2 side effects.

Discussion

There is considerable disease variability in patients with ICL. Many patients have recurrent opportunistic infections. Anti-microbial prophylaxis as used for HIV infection is often employed, but its benefit in ICL remains unclear. Similarly, IL-2 therapy has been used in patients with ICL. Several studies have evaluated IL-2 treatment of CD4+ lymphopenia because of HIV. Generally, these IL-2 treatments in HIV lymphopenia studies have revealed significant increases in CD4+ counts and possible clinical improvement in immunological function [1619]. From these large studies the side-effect profile of IL-2 in HIV CD4+ lymphopenic patients has been noted to include most commonly: fatigue, fever, chills, skin rash and nausea. In contrast, no studies have evaluated IL-2 treatment of ICL.

To our knowledge, only four case reports exist of IL-2 treatment for opportunistic infection associated with ICL. Cunningham-Rundles et al. described a 67-year-old woman with chronic severe myobacterial disease and ICL [12]. She was treated with pegylated, subcutaneous IL-2 (50 000 IU/m2 weekly) after failing anti-microbial and subcutaneous interferon (IFN)-γ therapy [12]. This low-dose IL-2 treatment resulted in the following: (1) myobacterial negative sputum cultures after 6 months; (2) significantly improved lung function; (3) gradually improved CD4+ cell counts to greater than 100 cells/mm3 after 1 year and reaching 200 cells/mm3 after 3 years; and (4) delayed improved T cell function with proliferation to mitogens returning in 1 year and proliferation to candida antigens after 4 years [12]. The patient in this report had received IL-2 treatment for 5·5 years and had not stopped IL-2 treatment.

Warnatz et al. reported a 65-year-old man treated with generalized, relapsing Herpes Zoster and intestinal candidiasis associated with ICL who was treated with pegylated, subcutaneous IL-2 (5 × 3 million IU with a 7-day pause) [13]. He received subcutaneous IL-2 after failing numerous anti-viral therapies and relapsing on subcutaneous IFN-γ therapy [13]. Five months after starting the IL-2 therapy the patient resolved his intestinal candidiasis, reported no H. zoster relapses and mildly improved CD4+ counts from 28 cells/mm3 to 93 cells/mm3[13].

Wilhem et al. reported a 33-year-old woman initially asymptomatic with ICL (CD4+ 130 cells/mm3) and decreased T cell proliferation capacity [14]; 3·5 years later she continued with ICL (CD4+ 136). She developed anaemia and interstitial nephritis and was found to have IgA and IgG gammopathies [14]. After failing a conventional chemotherapy regimen for multiple myeloma and induction chemotherapy followed by autologous stem cell rescue, the patient started subcutaneous IL-2 therapy at 380 000 IU per day and was titrated to 1 million IU per day with no relevant side effects [14]. Prior to beginning IL-2 therapy, her CD4+ count was 40 cells/mm3[14]. After 12 weeks of IL-2 therapy, when her treatment was 1 million IU IL-2 units daily, her CD4+ remained consistently above 300 cells/mm3, IgA and IgG gammopathies improved and renal function improved. She remained on IL-2 therapy for 2 years without additional side effects, stopping IL-2 therapy or infection relapse [14].

Most recently, Yilmaz-Demirdag et al. described the case of a 16-year-old male presenting with mental status changes and fever secondary to Cryptococcus neoformans meningitis who was found subsequently to have ICL (CD4+ 39 cells/mm3) [15]. After repeated relapses, even with prolonged anti-fungal regimens, the patient was started on IL-2 therapy initially at 50 000 IU/m2 twice per week and titrated up to 125 000 IU/m2 twice per week [15]. His CD4+ count increased from 202 cells/mm3 prior to starting IL-2 therapy to 262 cells/mm3 and 323 cells/mm3 at 5 and 9 months of IL-2 therapy respectively [15].

Similar to these previous ICL case reports, our patient improved clinically, increased his CD4+ cell counts and experienced a comparable side-effect profile to other ICL and HIV patients after beginning IL-2 treatment. Based on the Wilhem et al. case report, we selected IL-2 at 600 000 IU/day as this was the lowest, well-tolerated dose that produced a significant and undelayed increase in CD4+ cell counts [14]. We increased the dose as tolerated to achieve CD4+ counts greater than 300 cells/mm3, but unlike other case reports we titrated based on a three doses per week regimen, because of the patient's preference. The weekly 11 million IU (divided into three doses) our patient received exceeded the 7 million IU weekly (1 million daily) that Wilhem et al. reported and was fewer than the intermittent doses used in HIV trials [14,2427] (Table 1).

Table 1
A summary of all current case reports of idiopathic CD4+ lymphopenia (ICL)-associated infections and disorders treated with interleukin (IL)-2 including: clinical descriptions, pretreatment CD4+ counts, IL-2 dose, clinical response to IL-2 and post-IL-2 ...

Given the limited number of IL-2 treatment case reports in ICL-related opportunistic infections, few to no data exist for the exact mechanism of exogenous IL-2 in ICL patients. The few published ICL reports and numerous HIV studies have described the association of exogenous IL-2 with increased eosinophil, CD4+ and NK cell lines [1315,2527]. The importance of CD4+ and NK cells in host defence against MAI is well described in the current literature [10,11,28]. More specifically, in HIV-negative individuals, Shiratsuchi et al. found that IL-2 stimulation without lymphocytes was unable to inhibit intracellular monocyte M. avium growth, and IL-2 supplementation decreased M. avium growth only when lymphocytes were not present in excess [11]. Monocyte functional modulation is one of the probable many mechanisms by which IL-2 acts to augment not only lymphocyte numbers but also the broader immune response to MAI.

The IL-2 treatment correlated with improved CD4+ counts and resolution of MAI infection in our patient; however, the IL-2 treatment probably also improved his NK cell counts. Unfortunately, directly comparable peripheral or bone marrow results are not available for our patient. Given the unknown relationship between increased CD4+ and NK cell counts following exogenous IL-2 treatment and MAI clearance in ICL patients, we hypothesize that changes in cell counts and increased IL-2 levels both probably contributed to our patient's MAI clearance and continued defence against of other opportunistic infections.

In contrast to the other previous case reports, our patient's IL-2 therapy was discontinued (mainly at the patient's request), and we have followed him for another 9 months. Interestingly, our patient appeared to have a prolonged immunological laboratory response to IL-2 therapy 6 months following IL-2 discontinuation; however, this effect appears to have diminished in the most recent laboratory results. The reason for this observation may include the differing dosage amount and scheduling of our patient's IL-2 regimen compared with other ICL case reports and HIV studies [1215,2427]. Continued out-patient monitoring will be required to elucidate more fully the durability of the clinical and immunological response.

The safe and successful treatment of the patient in this case report supports IL-2 as a relatively safe and potentially effective treatment for ICL patients with opportunistic infections, especially when combined with conventional treatment regimens. The outcome of this case is in agreement with the limited number of other studies where IL-2 treatment was used successfully after failing more traditional regimens [1215]. Ideally, these results would lead to a more extensive study evaluating a larger patient population, comparing potential treatment regimens and following patients over an extended period of time. However, the low incidence of ICL and reported transient nature of some cases of ICL will be a challenge in designing such a clinical study [3,8]. Overall, these case reports support the use of IL-2 in select patients with ICL and opportunistic infections as a safe and potentially efficacious therapy with longer-term benefits.

Funding

This study was supported by the University of Texas Southwestern Medical Center.

Conflicts of interest

None reported.

Disclosure

None.

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