Primary Adrenal Insufficiency Triggered by Cytomegalovirus Infection after Obinutuzumab Plus Bendamustine Therapy for Follicular Lymphoma

Abstract

A 69-year-old man was diagnosed with follicular lymphoma (grade 3A). Obinutuzumab combined with bendamustine (OB) therapy was initiated as salvage chemotherapy. Nausea, abdominal pain, and hyponatremia appeared after six courses of OB therapy; cytomegalovirus (CMV) enteritis with primary adrenal insufficiency (PAI) was a complication. Ganciclovir and hydrocortisone were administered, and the clinical findings improved. PAI caused by CMV infection has mainly been reported in patients with acquired immunodeficiency syndrome. In the present case, the PAI triggered by CMV infection led to immunodeficiency after chemotherapy.

Introduction

Cytomegalovirus (CMV) disease is a condition caused by primary infection, reinfection, or reactivation of CMV, which belongs to the beta-herpesvirus subfamily (1). Inapparent infection during childhood and latency of the organism in the host throughout life can lead to reactivation and CMV disease during conditions of immunosuppression, such as hematopoietic stem cell transplantation, organ transplantation, acquired immunodeficiency syndrome (AIDS), corticosteroid therapy, and chemotherapy (1). Furthermore, CMV infection can result in pneumonia, enteritis, hepatitis, retinitis, and encephalitis (1).

Adrenal insufficiency (AI) is a disease caused by inadequate secretion of aldosterone, cortisol, and adrenal androgens and can be classified as primary due to adrenal disease or secondary due to hypothalamic or pituitary disease. The etiologies of primary AI (PAI) encompass autoimmune (idiopathic), infectious [tuberculosis, fungi, human immunodeficiency virus (HIV), syphilis, CMV], metastatic (lung cancer, breast cancer, gastric cancer, colorectal cancer, malignant lymphoma), hemorrhagic, infarction-related, and drug-induced (ketoconazole, fluconazole, rifampicin, phenytoin, barbiturates, and megestrol acetate).

Occasionally, CMV disease can induce PAI owing to adrenalitis. Pulakhandam et al. reported CMV disease of the adrenal glands in 84% of 37 autopsy cases of patients with AIDS and CMV infection (2). However, few cases of PAI due to CMV infection have been reported in patients with immunosuppressive diseases other than AIDS.

We herein report a rare case of PAI caused by CMV infection in a patient undergoing chemotherapy for follicular lymphoma.

Case Report

A 69-year-old man presented to our hospital with abdominal pain, nausea, and anorexia. The patient had a history of diabetes mellitus. In 2018, he had been diagnosed with follicular lymphoma grade 3A and clinical stage (CS) IV. He subsequently received one course of bendamustine and rituximab (BR) therapy as induction therapy but had his treatment interrupted due to development of a skin rash. Therefore, he received three courses of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in October 2018 and achieved a partial response.

The patient experienced a first relapse, CS III, in November 2019, and received four courses of BR therapy as a first salvage treatment, achieving a partial response, followed by rituximab maintenance. The patient then experienced a second relapse, CS III, in November 2020, and six courses of obinutuzumab with bendamustine (OB) were administered as a second salvage treatment. Grade 2 lymphocytopenia (748/μL) appeared after 1 course of OB therapy and grade 3 lymphocytopenia (242/μL) after 4 courses. While a complete response was attained, the patient experienced abdominal pain, nausea, and anorexia, starting at the end of July 2021. Consequently, the patient visited our hospital for an additional examination and treatment.

On admission, his blood pressure was 125/69 mmHg, body temperature was 36.1°C, heart rate was 76 beats/min, and oxygen saturation was 97% on ambient air. A physical examination revealed epigastric pain but no leg edema or pigmentation of the lips, nails, or skin. Blood tests revealed hyponatremia (125 mmol/L), leukocytopenia (2,400 cells/μL), and thrombocytopenia (84×10³ cells/μL) (Table 1). Furthermore, an early-morning resting hormone test showed a high adrenocorticotropic hormone (ACTH) level of 434 pg/mL, low cortisol level of 5.9 μg/dL, renin activity (PRA) of 0.3 ng/mL/h, and an aldosterone level below detection sensitivity. Subsequently, a rapid ACTH stimulation test was performed, and a cortisol level of 3.94 μg/dL led to a diagnosis of PAI.

Table 1.

Laboratory Data on Admission.

Complete blood count/Biochemistory						Endocrine test
WBC	2,400	/μL	CRP	0.32	mg/dL	TSH	1.43	μIU/mL
Neutro	62	%	Na	125	mmol/L	FT3	1.73	ng/dL
Lympho	22	%	K	4.2	mmol/L	FT4	2.18	pg/mL
Mono	15	%	Cl	94	mmol/L	ACTH	434	pg/mL
Eosino	0	%	Ca	8.8	mg/dL	PAC	<4.0	pg/mL
Baso	1	%	Osm	254	mOSM/KgH	Cortisol	5.9	μg/dL
Hb	13.1	g/dL	sIL-2R	1,030	U/mL	PRA	0.3	ng/mL/h
PLT	84	103/μL	β-D glucan	<5.0	pg/mL	AVP	1	pg/mL
AST	29	U/L	IgG	271	mg/dL	FBG	94	mg/dL
ALT	29	U/L	IgA	25	mg/dL	HbA1c	6.2	%
LDH	153	U/L	IgM	5	mg/dL	Infectious disease test
γ-GTP	51	U/L				CMV antigen	185	cells
BUN	15.8	mg/dL	Urinalysis			HIV-Ab	(-)
Cr	1.02	mg/dL	U-Osm	253	mOSM	RPR	(-)
CCr	62.8	mL/min	U-Na	35	mmol/L	TP-Ab	(-)
TP	5.3	g/dL	U-TP	(-)		T-SPOT®.TB	(-)
Alb	3.7	g/dL	U-BG	(-)

ACTH: adrenocorticotropic hormone, Alb: albumin, ALT: alanine aminotransferase, AVP: arginine vasopressin, AST: aspartate aminotransferase, BUN: blood urea nitrogen, Ca: calcium, CCr: creatinine clearance, CMV: cytomegalovirus, Cl: chlorine, Cr: creatinine, CRP: C-reactive protein, FBG: fasting blood glucose, FT3: free triiodothyronine, FT4: free thyroxine, γ-GTP: gamma-glutamyl transferase, Hb: hemoglobin, HbA1c: hemoglobin A1c, HIV-Ab: human immunodeficiency virus antibody, K: potassium, LDH: lactate dehydrogenase, Na: sodium, Osm: osmotic pressure, PAC: plasma aldosterone concentration, Plt: platelet, PRA: plasma renin activity, RPR: rapid plasma reagin, sIL-2R: soluble interleukin-2 receptor, TP: total protein, TP-Ab: Treponema pallidum antibody, TSH: thyroid-stimulating hormone, U-BG: urine-blood glucose, U-Na: urine-sodium, U-Osm: urine-osmotic pressure, U-TP: urine-total protein, WBC: white blood cell

Thyroid function tests were within the normal range: thyroid-stimulating hormone, 1.430 uIU/mL; free triiodothyronine, 2.18 pg/mL; free thyroxine, 1.73 ng/mL; anti-TPO antibody, 1.3 IU/mL; and antithyroglobulin antibody, ＜10.0 IU/mL. β-D glucan, HIV, and syphilis antibodies, and interferon-gamma release assay (T-SPOT^Ⓡ.TB; Oxford Immunotec, London, UK) tests were negative for infectious disease testing. In contrast, CMVpp65 antigen levels were elevated in 185/50,000 cells. Colonoscopy revealed no ulcer formation or bleeding, but edematous changes in the mucosa and redness were observed in the sigmoid colon. A colon mucosal biopsy revealed numerous large eosinophilic intranuclear inclusion bodies within enlarged fibroblasts and positive anti-CMV antibody immunostaining, which was compatible with CMV enteritis (Fig. 1).

Figure 1.

Pathological findings of a colon mucosal biopsy from an inflammatory polyp in the sigmoid colon. Numerous large eosinophilic intranuclear inclusion bodies within enlarged fibroblasts, ×400 (A). Immunohistochemistry staining: positive for anti-CMV antibody, ×400 (B).

No new drugs that could have caused PAI had been administered. Therefore, these results collectively confirmed the diagnosis of PAI caused by CMV disease. Computed tomography (CT) revealed no abnormalities. Adrenal magnetic resonance imaging showed no atrophy, masses, hemorrhaging, or infarcts in the adrenal glands bilaterally.

The clinical course of the patient is shown in Fig. 2. On day 9, ganciclovir (2.5 mg/kg×2/day) was administered intravenously for the treatment of CMV disease, and the abdominal pain and nausea were relieved by days 13 and 16, respectively. However, appetite loss, fatigue, and hyponatremia persisted, and concomitant intravenous hydrocortisone (400 mg/day) was started for treatment of PAI on day 17 (400 mg/day for 2 days, then tapered). The clinical symptoms were relieved on days 20 and 21, and hyponatremia improved to 138 mEq/L on day 23.

Figure 2.

Clinical course of the present case after the diagnosis of cytomegalovirus enteritis and primary adrenal insufficiency. *Day 0 means the day of admission. **The dosage of intravenous hydrocortisone was 400 mg/day for 2, followed by 300 mg/day for 2 days, 200 mg/day for 2 days, 100 mg/day for 2 days, and 50 mg/day for 2 days. Na: sodium, CMV: cytomegalovirus

The CMVpp65 antigen results also improved to 0/50,000 white blood cells, and the ACTH level decreased to 4.2 pg/mL. On day 18, ganciclovir was changed to oral valganciclovir (900 mg twice daily); the dose was reduced to 450 mg twice daily on day 30, and treatment was discontinued on day 37 because of neutropenia. The intravenous hydrocortisone was changed to oral hydrocortisone (20 mg/day) on day 27. Hyponatremia recurred on day 34. By day 37, a high ACTH level of 862 pg/mL and a low cortisol level of 5.45 μg/dL were noted, along with a high PRA of 7.8 ng/mL/h. Consequently, fludrocortisone (0.5 mg) was administered daily to compensate for mineralocorticoid deficiency.

On day 42, the CMVpp65 antigen was detected again (1/50,000 cells), and valganciclovir (450 mg/day) was resumed. Colonoscopy was performed on day 49, and the edematous changes of the mucosa and redness improved. As there was no symptom recurrence thereafter, the patient was discharged on day 50 of hospitalization, and treatment was continued on an outpatient basis. Valganciclovir (450 mg/day) was continued, and there was no relapse of cytomegalovirus antigenemia. In December 2021, the patient experienced a fourth relapse of follicular lymphoma and opted for the best supportive care, which was performed in accordance with his wishes.

Discussion

The patient developed CMV infection and PAI against a background of immunosuppression caused by chemotherapy for follicular lymphoma, and the combination of CMV treatment and hydrocortisone resulted in symptomatic improvement. PAI caused by CMV infection is rare, particularly in patients with chemotherapy-induced immunosuppression. When PAI-specific clinical symptoms and laboratory data, such as a fever, fatigue, and hyponatremia, appear during lymphoma treatment, AI complicating CMV infection should be considered.

PAI associated with CMV infection has been reported mainly in patients with AIDS, whereas there are few reports of CMV adrenalitis and PAI in immunocompromised states that are not due to HIV infection. As summarized in Table 2, there have been six and five cases of PAI due to CMV infection in patients with and without AIDS, respectively (3-8), including two cases of postrenal transplantation, one in a patient with systemic lupus erythematosus (SLE), one in an individual with acute lymphoblastic leukemia (ALL), and one in a patient with diffuse large B-cell lymphoma (9-13). The ages were 24 and 63 years old in the 2 postrenal transplant cases, 66 years in the SLE case, and 8 years in the ALL case. No comorbidities were observed in any of these five patients, but hyponatremia and hypotension were evident in all five cases, whereas hypoglycemia was noted in only two cases. Regarding CMV infection sites, retinitis was identified in one case, while hepatitis was found in two of the five cases. All patients were managed with anti-CMV treatment and corticosteroids, and three died. All three deceased patients underwent autopsies, which revealed hemorrhagic necrosis of the adrenal glands. Among the remaining patients, three underwent CT of the adrenal glands, and no abnormal findings were identified. Two patients developed irreversible AI and required permanent corticosteroid replacement therapy.

Table 2.

Summary of Cytomegalovirus-induced Primary Adrenal Insufficiency Cases.

References	Age	Sex	Past medical history	Underlying disease/status	Initial symptoms	Laboratory findings regarding adrenal insufficiency	Adrenal function and PRA/aldosterone levels	Image/pathological findings of adrenal glands	CMV diagnosis	Details of CMV infection	Treatment	Reversibility	Outcome
(2)	46	Man	Hemophilia B	AIDS	Hypotension, consciousness disturbance, vomiting, diarrhea	Hyponatremia (116 mEq/L), low plasma osmolarity	Low normal level of cortisol (3.9 μg/dL), increase of ACTH (204.8 pg/mL), low renin (0.06 ng/L/s), aldosterone (<28 pmol/L)	NA	Increase of serum anti-CMV antibody (IgG), positive for urinary CMV antigen	Retinitis	Hydrocortisone, ganciclovir	Irreversible	Alive
(3)	37	Man	NA	AIDS (with Kaposi’s sarcoma)	Anorexia, nausea, fatigue, weight loss, hypotension, fever	Hyponatremia (108 mmol/L), hyperkalaemia (5 mmol/L), low plasma osmolarity	Low normal level of cortisol (68.5 ng/mL), increase of ACTH (940 pg/mL), a very high level of renin (1,297 pg/mL), low aldosterone (67 pg/mL)	Normal (CT)	TBLB	Bronchitis, retinitis	Hydrocortisone, fluorohydrocortisone, ganciclovir	Reversible	Alive
(4)	42	Man	NA	AIDS (with pneumocystis pneumonia)	Asymptomatic (diastolic postural blood pressure deficit)	Hyponatremia (115 mmol/L), hyperkalaemia (7.3 mmol/L)	Low level of cortisol (24 nmol/L)	Normal (CT)	Positive for serum anti-CMV antibody (IgG) and PCR	NA	Hydrocortisone, fluorohydrocortisone, ganciclovir	NA	Alive
(5)	35	Man	NA	AIDS (with pneumocystis pneumonia)	Cough, fever, dyspnea, vomiting, hypotension	Hyponatremia (107 mEq/L), hypochloridemia (71 mEq/L), hyperkalaemia (6.8 mEq/L)	NA	Diffuse hemorrhage, necrosis with intranuclear inclusion bodies (autopsy)	CMV antigenemia	NA	Ganciclovir, prednisolone (no medication for adrenal insufficiency)	NA	Dead
(6)	46	Man	None	AIDS (with esophagus candidatis and pneumocystis pneumonia)	Skin pigmentation, fever, appetite loss, vomiting, hypotension	Hyponatremia (117 mEq/L), low plasma osmolarity	Low level of cortisol (0.3 μg/dL), high level of ACTH (678 pg/mL), low level of renin (0.8 ng/mL/h), aldosterone (≤10.0 pg/mL)	Normal (CT)	CMV antigenemia	NA	Ganciclovir (valganciclovir), hydrocortisone	NA	Alive
(7)	50	Man	None	AIDS (with esophagus candidatis and pneumocystis pneumonia)	Fever, cough, hypotension	Hyponatremia (130 mEq/L), low plasma osmolarity	Normal level of cortisol (16.7 μg/dL) with no elevation by ACTH stress test	NA	CMV antigenemia	Retinitis	Valganciclovir, hydrocortisone	NA	Alive
(8)	24	Woman	NA	Renal transplant recipient	Weakness, anorexia, weight loss, vague abdominal pain, muscle cramping, hypotension, hyperpigmentation	Slight hyponatremia (136 mEq/L) and hyperkalaemia (5 mEq/L)	NA	NA	Positive for serum anti-CMV antibody (IgM and IgG)	NA	Ganciclovir, hydrocortisone followed by prednisolone	NA	Alive
(9)	63	Man	NA	Renal transplant recipient	Fever, malaise, hypotension	Slight hyponatremia (136 mEq/L) and low level of fasting blood glucose (65mg/dL)	Low level of cortisol (2.4 μg/dL)	NA	Elevated CMV quantitative PCR	NA	Ganciclovir, hydrocortisone	NA	Alive
(10)	66	Woman	Renal tuberculosis	SLE	Fever, hypotension	NA	NA	Necrosis with intranuclear inclusion bodies (autopsy)	Elevated CMV antibody (CF)	Desseminated (liver, lung, retin)	Ganciclovir	NA	Dead
(11)	8	Man	NA	ALL	Fever, skinredness, asthenia, abdominal pain, nausea, vomiting, hypotension, cutaneous hyperpigmentation	Hyponatremia (125 mEq/L), hypoglycemia (60 mg/dL)	Low level of cortisol (2.4 μg/dL), high level of ACTH (581 pg/mL)	Normal (CT)	Positive for serum anti-CMV antibody (IgM and IgG), elevated CMV quantitative PCR	NA	Ganciclovir, prednisolone followed by fludrocortisone acetate	Irreversible	Alive
(12)	NA	NA	NA	DLBCL	Fever, hypotension	NA	NA	CMV infection of the lungs and several endocrine organs including the pituitary gland, pancreatic islets and adrenals (Autopsy)	Autopsy	Disseminated (lungs, pituitary gland, pancreatic islets and adrenals)	None	NA	Dead
Present case	69	Man	Diabetes mellitus	FL	Abdominal pain, nausea, anorexia	Hyponatremia (125 mmol/L)	Low level of cortisol (5.9 μg/dL), increase of ACTH (434 pg/mL), low aldosterone (below detection sensitivity)	Normal (CT, MRI)	CMV antigenemia	Enteritis	Hydrocortisone, ganciclovir	Irreversible	Alive

ACTH: adrenocorticotropic hormone, AIDS: acquired immune deficiency syndrome, ALL: acute lymphoblastic leukemia, CMV: cytomegalovirus, CT: computed tomography, DLBCL: diffuse large B-cell lymphoma, FL: follicular lymphoma, MRI: magnetic resonance imaging, SLE: systemic lupus erythematosus, TBLB: transbronchial lung biopsy

The present patient was over 60 years old and had received both rituximab and obinutuzumab, which may be associated with a high risk of CMV infection. In addition, the incidence of CMV infection is reportedly increased by chemotherapy with bendamustine-containing regimens (14-17). Bendamustine-containing regimens are more likely to cause a decrease in CD4-positive lymphocytes than other regimens, and CMV infection is more likely to occur regardless of neutropenia or glucocorticoid use (14-17). The decrease in CD4-positive lymphocytes with bendamustine peaks between cycles 2 and 5, and it takes seven to nine months to return to baseline after the end of treatment (18), suggesting that our patient's CD4-positive lymphocyte count was at its lowest, creating a high risk for CMV infection.

Regarding the reversibility of PAI, many cases are irreversible and require long-term corticosteroid replacement, whereas one reversible case after relief from CMV infection has been reported (4). In the case reported as reversible, reverse transcriptase inhibitors were initiated before the onset of CMV infection and PAI, suggesting the potential for a PAI onset through immunological responses to CMV infection associated with immune reconstitution. Although pathological retrieval was not feasible in the present case, the patient exhibited no factors that might have led to immune reactivation; we therefore deemed the PAI to be irreversible, as evidenced by the early recurrence of elevated ACTH and cortisol levels following the resolution of the CMV infection.

In summary, it is important to note that AI associated with CMV infection can occur not only in cases of AIDS but also in immunodeficient states associated with chemotherapy. Although treatment with corticosteroids and anti-CMV drugs is effective in improving the clinical symptoms, the reversibility of PAI caused by CMV infection remains controversial. The further accumulation of similar cases is required.

The authors state that they have no Conflict of Interest (COI).