Acute CMV hepatitis in an immunocompetent patient

Abstract

A previously well and immunocompetent 64-year-old woman presented with fever of unknown origin and acute hepatitis. Besides headache and nausea, she had no other symptoms. Her clinical examination was unremarkable with no clear focus of infection. She was thoroughly investigated and her biochemical profile suggested a viral or autoimmune aetiology. Multiple imaging modalities gave no further insight. Her serology and subsequent nucleic acid amplification indicated reactivation of latent cytomegalovirus (CMV). Her symptoms resolved with supportive care and no anti-viral therapy was needed. This case report highlights CMV reactivation leading to acute hepatitis in a well, immunocompetent patient.

Background

Cytomegalovirus (CMV) is a member of the Herpesviridae family. It generally affects adolescents and has a benign asymptomatic course.¹ It usually is of clinical concern in immunosuppressed patients, causing severe and even fatal primary infection or reactivation.¹

CMV is often neglected as a cause of febrile illness in the immunocompetent leading to extensive investigations and inappropriate therapy.¹ Case reports have featured primary CMV infection leading to liver involvement in immunocompetent individuals, ranging from self-limiting diseases to fulminant hepatic failure.² Literature has also drew attention to severe CMV reactivation among immunocompetent patients who are critically unwell, causing prolonged intensive care unit (ICU) stay and systemic involvement.³ Nonetheless, CMV reactivation in a well, immunocompetent patient causing hepatitis has been rarely described before.

We report a case of reactivation of CMV in an immunocompetent host presenting as a fever of unknown origin and elevated liver enzymes, highlighting the unusual presentation of CMV reactivation related hepatitis in a well, immunocompetent patient. This case demonstrates the approach of fever and liver derangement in an immunocompetent patient. The report then discusses current literature on the pathophysiology of CMV reactivation in immunocompetent patients as well as the role of antiviral treatment in CMV hepatitis.

Case presentation

A previously well 64-year-old woman presented to her general practitioner (GP) with a 1 week history of lethargy and fevers. At that time, she had elevated liver enzymes and aseptic pyuria. She was commenced on a course of cephalexin for a putative urinary tract infection. Follow-up with her GP showed significant derangement of her liver enzymes, ongoing fever and a worsening clinical state. She was referred to the regional general hospital for further workup and treatment.

On presentation to hospital, she was febrile, unwell and lethargic. She reported nausea and headache. She had no shortness of breath, cough, itch or confusion. She had no significant medical history part from being overweight with a body mass index (BMI) of 30. She took no regular medications. She had no recent travel, nor had she been exposed to sick contacts, pets or livestock. She was life-long non-smoker and never consumed alcohol. On examination, she had not developed icterus, she had a soft abdomen with no organomegaly and had no lymphadenopathy. Similarly, cardiorespiratory, neurological, musculoskeletal examination were unremarkable.

Investigations

Her initial workup showed deranged liver function and raised inflammatory markers. Lymphocyte count showed a mild leucocytosis. Her renal function and electrolytes were unremarkable. There were elevated liver enzymes as well as a significantly raised ferritin in keeping with inflammation (refer to table 1). She had an elevated lactate dehydrogenase (939) and an associated increase of inflammatory markers (CRP 61 and ESR 32).

Table 1.

Haematology and biochemistry results

	19/02/2019	22/02/2019	26/02/2019	9/04/2019	Reference range
	Inpatient day 2	Inpatient day 5	Inpatient day 9	2 months follow-up
Hb	121.00	126	111	123	115–135 g/L
Plt	275	329	354	357	150–450×109/L
WCC	9.6	8.6	14.26	7.22	4.0–11.0×109/L
Neutro	2.47	4.24	5.56	2.77	2.0–8.0×109/L
Lympho	3.94	3.95	7.86	3.66	1.0–4.0×109/L
CRP	56	51	26	4.9	<3.0 mg/L
Ferritin	2640			80	15–200 μg/L
Billi	8	8	7	6	<21 μmol/L
ALT	1130	768	402	72	5–40 U/L
AST	595			44	5–35 U/L
ALP	117	134	105	50	30–110 U/L
GGT	271	289	204	27	5–50 U/L
Alb	34	33	29	41	35–50 g/L
CMV IgG CMIA	13.7
CMV IgM EIA	Positive
CMV viral load		7.62×103 copies/mL		<2.00x101 copies/mL	<20 copies/mL
EBV IgM	Positive
EBV IgG	Positive
EBV viral load				not detectable
Heterophile Ab Slide	Negative
Anti-EBV nuclear ag	positive
ANA	15, homogenous pattern				<7 IU/ml
other autoimmune panel	dsDNA 2 ANCA 2 AMA 0 IgA 3.74 IgG7.5 IgM 2.2 anti-LKM antibody 0 Anti-Smooth muscle antibody 2 IgA transglutaminase 1				<7IU/mL <4 units 0 = not detlected 0.60-3.40g/L 5.8-13.7g/L 0.30-1.70g/L 0= not detected 2= moderate positive <7 U/ml
MRCP	No intra or extra hepatic biliary dilatation. No MRI features of Cholangitis or liver abscess. No CBD calculi or stricture.
SPECT	Mild degenerative pattern of update in both shoulders sternoclavicular and manubrial sternal joints noted. Unremarkable distribution of tracer elsewhere. No evidence of osteoblastic metastasis. No evidence of inflammatory arthropathy.

Alb, albumin; ALT, alanine transaminase; AMA, Anti-mitochondrial antibody; AST, aspartate aminotransferase; CMV, cytomegalovirus; CRP, C reactive protein; GGT, gamma-glutamyl transferase; Hb, haemoglobin; Plt, platelet; WCC, white cell count.

Liver imaging including ultrasound and MRCP showed no duct dilation or underlying aetiology. A CT scan of chest/abdomen/pelvis found no focus but did indicate the presence of fatty infiltrates in her liver consistent with non-alcoholic fatty liver disease (NAFLD).

Patient was initially worked up for infectious causes. Blood culture and urine culture were unremarkable. Hepatitis viral serology (hepatitis A, B, C, D, E) and HIV serology were all negative. Brucella, treponema, rickettsia and Q fever serology were also negative. Thick and thin films indicated atypical lymphocytes. Antigen testing of Plasmodium falciparum was negative, as was α-1 antitrypsin level. A CT-SPECT scan was unremarkable.

Autoimmune panel was done. There was a homogenous pattern of ANA with a moderately positive smooth muscle antibody. Antimitochondrial antibody was negative. She had normal immunoglobulins and normal peripheral flow cytometry.

Her paracetamol levels and urine drug screen on presentation were unremarkable.

Eventually, both IgG and IgM of EBV and CMV returned positive. In time, viral CMV nucleic acid testing was positive and she has a positive anti-EBV nuclear antigen and a negative heterophile antibody slide. It was thought she had a likely CMV reactivation and a previous EBV infection with a false positive IgM. The positive EBV IgM was thought to be due to cross-reaction with CMV infection, on discussion with biochemical pathologist. Unfortunately, viral capsid antigen IgG and VCA IgM was not performed to further confirm the cross-reaction.

Differential diagnosis

The patient was thought to be immune competent. Other than a BMI of 30, the patient has no significant previous medical history and is not on immunosuppressants. Additionally, she also had a negative HIV serology, a normal flow cytometry and her immunoglobulins were within normal limits.

Autoimmune hepatitis was one of the differentials considering the raised homogenous ANA and raised smooth muscle antibody. Antimitochondrial antibody was negative. The empirical treatment for autoimmune hepatitis was withheld while awaiting viral serology.

As her viral serology and subsequent nucleic acid testing clearly pointed to a diagnosis of CMV hepatitis. With her raised ANA was deemed to be an incidental finding. It was also noted that her raised EBV IgM was likely due to cross-reactivity, which was well reported in literature.⁴

Haemophagocytic lymphohistiocytosis (HLH) was also considered given her raised ferritin. HLH is a life-threatening syndrome due to aggressive immune system activity. It can have a variety of presentation febrile episodes and liver failure. However the patient did not fulfil the diagnostic criteria other than raised ferritin and fever. We considered a bone marrow biopsy, NK cell activity and CD25 levels. However, in consultation with haematology these investigations deferred until the primary panel of tests returned.

A liver biopsy can be considered if the diagnosis was unclear or patient deteriorates. However, the patient had made reassuring recovery themselves and diagnosis was clear after non-invasive investigations in this case. Therefore liver biopsy was not done.

Treatment

The patient was treated supportively with intravenous fluid and ibuprofen. All antibiotics were withheld throughout her 10-day admission. Antiviral therapy with ganciclovir was not given as she improved clinically and biochemically. She was discharged after being afebrile for 48 hours with plans of an outpatient follow-up.

The patient was followed by her GP, and her liver enzymes and inflammatory markers continued to normalise. Her lethargy improved over a few weeks and she has been asymptomatic. Four months after admission her alanine transaminase and ASL were still raised likely secondary to underlying NAFLD.

Discussion

Primary CMV infection is common across the globe, with more than 40% of adults affected by the fourth decade of life.¹ The primary infection is usually subclinical for immunocompetent individuals with malaise, fever and mild liver-function abnormalities.¹ Acute CMV hepatitis is an unusual manifestation of primary CMV infection, however, it has been reported in a number of studies, including a case study by Alexander et al⁵ in BMJ case report 2013.⁶

CMV primary infection and reactivation in immunocompromised patients, such as patients with a history of transplant or AIDS infection, can be severe and even fatal.¹ Systemic reviews demonstrated that CMV reactivation have a worse impact on host compared with primary CMV viremia.⁷ Recent reports have highlighted severe CMV reactivation among immunocompetent critically ill individuals in ICU settings, which is associated with prolonged ICU stay and increased mortality.³ CMV is usually maintained in a latent state within monocytes and dendritic cells.³ Clari et al⁸ showed CMV infection in critically ill patients was associated with undetectable interferon-gamma T cell responses. CMV infection is associated with immune system paralysis in septic patients and cytokine storm associated with a critical illness.³ During sepsis, burns, trauma or major surgery, the CMV genes are expressed and viral replication is initiated, causing invasions in the lungs, kidney, liver, bone marrow and intestine.³

CMV was reported to cause fatal fulminant hepatic failure among immunocompetent individuals in few cases, and these infections were thought to be caused by primary infections.⁸ To he best of our knowledge, CMV reactivation in a well, immunocompetent patient causing hepatitis has not been specifically reported. Unlike the previous reports of CMV reactivation in immunocompetent critically ill individuals, our patient was not critically unwell, nor had she received recent major surgeries. Positive IgG and IgM were suggestive the reactivation nature of her CMV disease. Similarly, CMV reactivation is found affecting other organs and system in well, immunocompetent patients. CMV anterior uveitis, a well-known ocular inflammatory disease, is thought to be due to ocular CMV reactivation in well, immunocompetent individuals.⁹ CMV was also found in the mucosa wall among immunocompetent host with colitis, with unknown significance.¹⁰ These cases are intriguing and challenge us to reconsider the pathogenesis in CMV reactivation in well and immunocompetent individuals.

The treatment of CMV disease in immunocompetent individuals has been highly debated. Primary CMV infection in immunocompetent individuals is usually self-limiting and does not require treatment.¹ Eddleston et al¹ suggested a potential benefit in anti-CMV treatment for severe CMV disease in immunocompetent individuals. Notably, for patients with multiorgan involvement, 5 of 6 received treatment of either ganciclovir or foscarnet recovered, while only 4 out of 18 patients who did not receive anti-CMV treatment survived.¹ Recent literature took an interest in the treatment and prophylactic treatment of CMV disease among immunocompetent critically ill individuals in ICU settings. Cowley et al¹¹ led a randomised Clinical Trial on the safety and efficacy of anti-viral therapy for the prevention of CMV reactivation in 124 immunocompetent critically ill patients. The study found anti-viral prophylaxis with valacyclovir or low-dose valganciclovir suppresses CMV reaction in patients with a critical illness.¹¹ However, some researchers also highlighted the diagnostic challenge of CMV with CMV PCR, namely the high sensitive test may pick up innocent viral shedding as CMV infections, leading to overtreatment with anti CMV medications.¹² Papazian, therefore, recommended treatment for CMV should only be indicated for cases with lung infiltrates and other risk factors, as CMV may be only a bystander or innocent viral shedding in some cases.¹³ In our case, the patient recovered from hepatitis with supportive therapy without anti-viral medications. This aligns well with the current recommendation of treatment of CMV disease among immunocompetent individuals; however, one may consider the use of anti CMV medications, if the patient hepatitis was protracted.

Learning points.

• Reactivation of cytomegalovirus (CMV) in immunocompetent patients can lead to severe illness with multiorgan involvement.

• CMV infection or reactivation should be in the working diagnosis for fever of unknown origin

• In severe CMV infection, one should have a low threshold to start antiviral therapy.

• The reactivation of CMV is rare in an immunocompetent individual.