Septic shock due to cytomegalovirus colitis associated with rituximab use: A case report

Abstract

BACKGROUND

Cytomegalovirus (CMV) infections can cause significant morbidity and mortality in immunocompromised individuals. CMV targets dysfunctional lymphocytes. Chronic rituximab (RTX) therapy can cause B-lymphocyte dysfunction, increasing CMV risk. Rarely, CMV infections present with critical illness such as septic shock.

CASE SUMMARY

A 64-year-old African American woman presented with generalized weakness and non-bloody watery diarrhea of 4-6 weeks duration. She did not have nausea, vomiting or, abdominal pain. She had been on monthly RTX infusions for neuromyelitis optica. She was admitted for septic shock due to pancolitis. Blood investigations suggested pancytopenia and serology detected significantly elevated CMV DNA. Valganciclovir treatment led to disease resolution.

CONCLUSION

This case illustrates an extremely rare case of CMV colitis associated with RTX use presenting with septic shock. High suspicion for rare opportunistic infections is imperative in individuals with long-term RTX use.

Key Words: Cytomegalovirus colitis; Rituximab use; Immunocompromised status; Septic shock; Pancytopenia; Case report

Core Tip: With the increasing use of biologics in medicine, there has been an emergence of opportunistic infections. Cytomegalovirus (CMV) infections remain asymptomatic or cause only mild symptoms in most immunocompetent adults. However, it can cause infectious complications in immunocompromised individuals-especially those with defective T-lymphocyte function. Rituximab (RTX) use is associated with B-lymphocyte depletion and increased risk of infections. However, CMV infections after long-term RTX are uncommon. Our case describes septic shock due to CMV colitis associated with RTX use which is an extremely rare entity. It highlights the need for consideration of rare opportunistic infections in all patients on biologics.

INTRODUCTION

Most adults (40%-100%) have been infected and are carriers of cytomegalovirus (CMV)[1-3]. In the immunocompetent, CMV’s acute presentation is asymptomatic. Once infected, CMV remains latent in the host’s cells indefinitely[1-3]. If an infected person becomes immunocompromised, their latent CMV infection can reactivate and present itself in a variety of manifestations including pneumonia, esophagitis, retinitis, hepatitis, and colitis[1,2].

Rituximab (RTX)- an anti-CD20 antibody, is used to treat patients with various autoimmune conditions[3]. Its use can lead to adverse effects, the most notable being increased infection risk due to its effect on humoral immunity[3-5]. A rare complication of long-term RTX use can be the development of opportunistic infections, like in our case, CMV. Some studies have found an association between RTX use and the development of low levels of immunoglobulins, increasing susceptibility for opportunistic infections[2,3,6].

CASE PRESENTATION

Chief complaints

A 64-year-old African American woman presented to the emergency room with generalized weakness for 24 hours. She complained of non-bloody, watery diarrhea of 4-6 times per day, for 4-6 weeks duration.

History of present illness

She denied nausea, vomiting, abdominal pain, fever, chills, or rash, as well as recent travel, consumption of contaminated food, or sick contacts.

History of past illness

She had a history of neuromyelitis optica (on RTX), hyperlipidemia (on atorvastatin), and diabetes mellitus type II (on metformin and glipizide). Colonoscopy 10 years ago was unremarkable.

Personal and family history

Past and family history were negative for neoplasm or autoimmune disease. She denied tobacco, alcohol, or illicit drug use.

Physical examination

On initial assessment, the patient was tachycardic (119/min) and hypotensive (81/47 mmHg) without fever or hypoxia on room air. Physical examination was remarkable for lethargy, dry oral cavity, and conjunctival pallor. Abdomen was soft, non-tender, and non-distended with bowel sounds in all four quadrants.

Laboratory examinations

Laboratory investigations were significant for pancytopenia, hypoglycemia, acute kidney injury, and lactic acidosis (Table 1).

Table 1 Lab investigations on admission and during hospital stay.

	Patient values	Normal values
White blood cell count (× 103 cells/mL)	1.35	4.8-10.8
Red blood cell count (million cells/mL)	2.59	4.2-5.4
Hemoglobin (mmol/L)	4.96	8.7-11.2
Hematocrit (%)	25.6	37.0-47.0
Mean corpuscular volume (FL)	98.8	81-99
Mean corpuscular hemoglobin (PG)	30.9	27-31
Mean corpuscular hemoglobin concentration (g/dL)	31.3	33-37
Red cell distribution width (%)	14.9	11.5-14.5
Platelet count (× 1000 cells/mL)	16	130-400
Neutrophils (%)	37.1	42.2-75.2
Lymphocytes (%)	57.0	20.5-51.5
Monocytes (%)	3.7	1.7-9.3
Percentage reticulocyte count (%)	0.57	0.8-2.1
Sodium (mmol/L)	137	135-145
Potassium (mmol/L)	4.7	3.5-5
Chloride (mmol/L)	98	98-105
Blood urea nitrogen	5.36	3.6-7.1
Serum creatinine (μmol/L)	97.26	44-97
Aspartate transaminase (U/L)	74	10-30
Alanine transaminase (U/L)	18	10-36
Alkaline phosphatase (U/L)	53	32-104
Erythrocyte sedimentation rate (mm/hour)	56	0-20
C- reactive protein (mg/L)	160.98	0-5
Cytomegalovirus DNA by polymerase chain reaction	14800 IU/mL	Undetected
Immunoglobulin M (g/L)	10	40-230
Immunoglobulin A (g/L)	239	70-400
Immunoglobulin G (g/L)	1200	700-1600
Blood culture	Negative	Negative
Stool tests: Clostridioides difficile, Escherichia coli, Shiga toxin, Cryptosporidium, Cyclospora, Adenovirus, Norovirus, Rotavirus, Giardia, Entamoeba	Negative	Negative
Peripheral smear	Normocytic normochromic anemia, thrombocytopenia	No anemia or thrombocytopenia
Bone marrow and flow cytometry	Hypocellular (10%) bone marrow with mild erythroid hyperplasia. Negative for monoclonal plasma cell or blast cell population	Normal cellularity without any monoclonal or blast cell population

Imaging examinations

Computed tomography scan of the abdomen and pelvis with contrast detected diffuse thickening of the colonic wall with peri-colonic stranding consistent with pancolitis (Figure 1).

Figure 1  Coronal and transverse sections of a computerized tomographic scan of abdomen and pelvis without contrast showing pan-colitis with thickening of the intestinal wall and peri-colonic stranding (arrowhead and arrow).

FINAL DIAGNOSIS

She was diagnosed with septic shock due to acute colitis and admitted to the critical care unit with intravenous fluids, vasopressor, and antibiotics.

TREATMENT

Stool studies ruled out Clostridioides difficile, Escherichia coli, Shigella, and Salmonella among other infections (Table 1). Blood cultures and hepatitis panel were negative. Filgrastim injections were started to address pancytopenia. CMV serology demonstrated elevated CMV DNA. The patient could not undergo colonoscopy for tissue biopsy due to thrombocytopenia. Hence, the diagnosis of CMV colitis due to RTX was made based on clinical presentation and serology.

OUTCOME AND FOLLOW-UP

Valganciclovir was started. Her diarrhea and pancytopenia resolved over the next 7 days. She was discharged home in stable condition.

DISCUSSION

CMV infects about 40%-100% of the population by the adult life[1,2]. In the immunocompetent, it is mostly asymptomatic or presents as a mild mononucleosis-like syndrome (Figure 2)[1-3]. Once the primary infection resolves, CMV remains latent in its host indefinitely[1]. Most CMV disease manifestations are due to viral reactivation which commonly occurs when an infected individual becomes immunocompromised[1,2]. For example in solid organ and bone marrow transplant recipients, and HIV patients, reactivation of CMV can manifest as pneumonia, esophagitis, retinitis, hepatitis, and colitis[1,3].

Figure 2 Pathophysiology of cytomegalovirus infections in immunocompetent and immunocompromised individuals. CMV: Cytomegalovirus.

CMV disease in immunocompromised individuals occurs through one of three different pathways: Acute infection, latent viral reactivation, or reinfection with a new viral strain[1]. Most commonly, reactivation is due to dysfunctional or inadequate numbers of T lymphocytes and natural killer cells[1,2]. Disease severity is closely related to the patient’s degree of immunodeficiency[1,2].

RTX is an anti-CD20 antibody used for the treatment of various conditions including non-Hodgkin’s lymphoma, rheumatoid arthritis, and neuromyelitis optica[3-6]. The most notable adverse effect of its use is an increased risk of infection[3-6] which is primarily related to B lymphocyte depletion[1,2]. One study found that 30% of patients reported side effects were infectious in nature[3]. Of these, 63% were bacterial infections, 33% viral and 3.3% fungal[3]. Despite an increased risk of infection, opportunistic infections are uncommon, highlighting the uniqueness of this case.

A rare complication of RTX is CMV reactivation. Although CMV primarily affects T lymphocytes, humoral immunity plays a critical role in suppressing CMV[2,3,6]. A literature review explored the association between CMV and RTX.

We queried PubMed and Google Scholar for articles related to CMV colitis induced by chronic RTX use. Key words included: Cytomegalovirus, CMV, colitis and rituximab. Articles were case reports or series written in English involving adult patients. The articles needed to include RTX use and definitive CMV diagnosis via biopsy or serology. Only one case of CMV colitis associated with RTX use was found[3]. All other cases demonstrated either non-colitis CMV manifestations- encephalitis, pneumonitis, retinitis, gastritis, and death[7,8]; or were precipitated by concomitant use of multiple immunosuppressing drugs such as bendamustine or fludarabine[8-10]. Unfortunately, these multi-drug regimens complicated the cases and made it impossible to determine if RTX or another medication induced the CMV infection.

Only Vallet et al[3] case report demonstrated RTX induced CMV-colitis. Like our report, their patient was a middle-aged woman who developed CMV colitis after 2 cycles of RTX, although our patient was on RTX for > 3 years. The patient in our case had neuromyelitis optica while theirs suffered from rheumatoid arthritis. Both experienced hypogammaglobulinemia, hypo-IgM in our patient while hypo-IgG in theirs. There was no description of the severity of the symptoms in Vallet et al’s report whereas our case had septic shock requiring critical care management. Both patients eventually improved with valganciclovir[3].

Other reports have found that hypogammaglobulinemia increases the risk of CMV reactivation[3-6]. One paper reported CMV in five patients with hypo-IgG[3]. Repeated RTX treatments increase patients’ risk of developing hypo-IgG[4]. Our case is unique because our patient had hypo-IgM and normal IgG. Studies have found an association between RTX use and hypo-IgM leading to an increased risk of infections; however, there are no cases of RTX induced hypo-IgM leading to CMV colitis[4,5]. Low IgM levels were strongly associated with sepsis for those on RTX[3-5]. Similarly, our patient suffered from colitis and sepsis.

CONCLUSION

Overall, this case illustrates a rare case of CMV colitis associated with RTX use presenting with septic shock. High suspicion for rare opportunistic infections is imperative in individuals with RTX use. Immunocompromised patients with gastrointestinal signs and symptoms should be evaluated for possible opportunistic infections such as CMV.