Severe Adenovirus Infection with SARS-CoV-2 Co-infection

Abstract

A 34-year-old man with no medical history presented to our hospital with a sore throat and difficult oral intake for two days before admission. He had various symptoms, including red eyes, ocular discharge, a fever, and intraoral ulcers, and he was admitted immediately. The polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive, as was the adenovirus antigen test of the pharyngeal swab fluid, suggesting overlapping adenovirus and SARS-CoV-2 infections. The patient's condition improved with conservative treatment. This case of severe and varied symptoms caused by co-infection with adenovirus and SARS-CoV-2 has been previously reported.

Introduction

Human adenoviruses (AdVs) are non-enveloped icosahedral viruses with double-stranded DNA and include 52 serotypes that have been classified into 7 species (A-G) (1). Among the serotypes, AdV-B and C most commonly cause respiratory infections and conjunctivitis, whereas AdV-D is one of the major causes of epidemic keratoconjunctivitis (1). Recently, there have been concerns about the simultaneous spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza, and synergistic effects, such as an increased risk of death due to co-infection with SARS-CoV-2 and influenza, have been noted (2). Similarly, co-infections with SARS-CoV-2 and various respiratory pathogens, including AdVs, have been reported (2).

We herein report a young man with severe and varied symptoms caused by an AdV infection due to overlapping AdV and SARS-CoV-2 infections.

Case Report

A 34-year-old man with no significant medical history presented to his local doctor 2 days before admission with bilateral hyperemia, ocular discharge, tearing, a fever, sore throat, cough, and oral ulcers. The following day, the same doctor suspected herpes simplex virus infection and prescribed valacyclovir and acetaminophen. The patient visited our emergency room with complaints of sore throat and difficulty in oral intake.

The patient had a smoking history of 15 cigarettes per day for 15 years and was not taking any regular oral medications other than valacyclovir and acetaminophen prescribed by the previous physician and no new herbal medicines. Although his two children, both of whom were elementary school students, had been infected with coronavirus disease 2019 (COVID-19) about two weeks earlier, their symptoms had already improved, and there was no outbreak of another viral infection at the time of admission, including at the patient's workplace. He also had no history of travel to mountains, rivers, overseas, or soil exposure.

On the day of admission, the patient had a fever with a temperature of 38.0°C, SpO₂ of 97% on room air, ocular conjunctival hyperemia and discharge, and erosions and ulcers with white fur that were widely distributed on the oral mucosa; even slightly opening the mouth caused severe pain (Fig. 1A-C). Vesicles with scattered erythema on the trunk and extremities, erythema and erosions at the base of the glans penis, and pustular deposits at the urethral opening were observed.

Figure 1.

Physical examination. On the day of hospitalization, the patient has ocular conjunctival hyperemia and discharge, and erosions and ulcers with white fur are widely distributed on the oral mucosa (A, B). There are vesicles with scattered erythema on the extremities (C). These findings are improved on the day of discharge (D-F).

Laboratory findings showed severe inflammation, with a white blood cell (WBC) count of 16,000 /μL and C-reactive protein level of 18.9 mg/dL, along with mild liver dysfunction appearing as a manifestation of a systemic viral infection (Table). He was diagnosed with mild COVID-19 based on a positive SARS-CoV-2 polymerase chain reaction (PCR) using a nasopharyngeal swab and no infiltration shadows on chest radiography and computed tomography, and he was admitted to the hospital.

Table.

Laboratory Examinations.

Blood cell counts			Infection
WBC	16.0	×103/μL	Blood
RBC	5.82	×106/μL	Anti-AdV Ab titers (CF)	1:8
Hb	16.7	g/dL	Anti-MP Ab titers (PA)	1:40
PLT	29.1	×104/μL	Throat swab
Biochemistry			SARS-CoV-2 PCR	Positive
CRP	18.9	mg/dL	Anti-AdV Ag	Positive
TP	7.3	g/dL	MP DNA	Negative
Alb	4.1	g/dL	Urethra swab
T-Bil	2.5	mg/dL	Anti-AdV Ag	Negative
AST	30	U/L	AdV PCR	Negative
ALT	80	U/L	Urine
CPK	67	U/L	Neisseria gonorrhoeae PCR	Negative
LDH	207	U/L	Chlamydia trachomatis PCR	Negative
Cr	0.78	mg/dL	Blister
Na	140	mEq/L	HSV (FA)	Negative
K	3.8	mEq/L	VZV	Negative
Serology
ANA	Negative		Culture
MPO-ANCA	<1.0	U/mL	Blood	Negative
PR3-ANCA	<0.6	U/mL	Ocular secretion	Negative
Anti-TP* Ab	Negative		Throat swab	α streptococcus
Anti-HIV Ab	Negative		Genital swab	S. dysgalactiae
			Urine	Group G Streptococcus
Urinalysis
Protein	2+
Blood	-

Ab: antibody, AdV: adenovirus, Ag: antigen, Alb: albumin, ALT: alanine aminotransferase, ANA: antinuclear antibody, ANCA: anti-neutrophil cytoplasmic antibody, AST: aspartate aminotransferase, CF: complement fixation test, CPK: creatine phosphokinase, Cr: creatinine, CRP: C-reactive protein, FA: fluorescent antibody, Hb: hemoglobin, HIV: human immunodeficiency virus, HSV: herpes simplex virus, LDH: lactate dehydrogenase, MP: Mycoplasma pneumoniae, PA: particle agglutination, PLT: platelet, PCR: polymerase chain reaction, RBC: red blood cell, T-Bil: total bilirubin, TP: total protein, TP*: Treponema pallidum, VZV: varicella zoster virus, WBC: white blood cell

As he had no risk factors for severe outcomes, he was treated conservatively without specific therapy for COVID-19. The combination of oral ulcers and urethritis suggested the possibility of gonorrheal and chlamydial infections. In addition, the presence of a fever with a rash raised the possibility of other sexually transmitted infections, such as infectious mononucleosis, syphilis, or human immunodeficiency virus (HIV) infection. Therefore, treatment with intravenous ceftriaxone 2 g daily and minocycline 200 mg daily was initiated.

The AdV antigen (Ag) test using an immunochromatographic assay (ALSONIC Adeno; Alfresa Pharma, Osaka, Japan) of a pharyngeal swab performed on the fourth day after admission was positive. Five days after admission, the AdV antibody (Ab) blood test using complement fixation was positive (8-fold), whereas urine PCR tests for Neisseria gonorrhoeae and Chlamydia trachomatis were negative, as were the Mycoplasma Ab blood test and herpes virus and herpes zoster Ag tests of vesicular fluid (Table). Based on the results, severe AdV infection (3) with SARS-CoV-2 co-infection was diagnosed, so the administration of two antimicrobial agents (ceftriaxone and minocycline) was discontinued, and only maintenance therapy with supplemental fluids and analgesics was continued.

The patient was able to drink water and resume oral intake 10 days after admission. Eleven days after admission, he was able to eat sufficient food and was discharged home, meeting the criteria for ending the isolation for COVID-19 (Fig. 2). At that time, the hyperemia, ocular discharge, and oral ulceration in both eyes had improved greatly, and his skin rash had faded (Fig. 1D, E).

Figure 2.

Clinical course. Adm: admission, CRP: C-reactive protein, CTRX: ceftriaxone, Dis: discharge, MINO: minocycline, WBC: white blood cell

Discussion

In the present case, a patient co-infected with AdV+SARS-CoV-2, probably of the Omicron variant (BA.1, BA.2) of SARS-CoV-2, which was prevalent at that time, had severe symptoms of a pharyngo-conjunctival fever, which are mainly seen with AdV-1,2,3,5,6 infections. Conjunctivitis is accompanied by hyperemia and ocular discharge, similar to the epidemic keratoconjunctivitis seen in AdV-8,19,37,54 infections (1).

Simultaneous viral infections may evoke cytokine storm, which puts patients at risk of severe disease and leads to diverse clinical manifestations (4). Previous studies showed that 46.6-52.2% of COVID-19 patients were co-infected with ≥1 respiratory pathogens. Compared to bacterial co-infection (7%), viral co-infections are less common (3%), and approximately 5-7% of these viral co-infections are associated with adenoviruses (5). Swets et al. found that, in 136 patients with SARS-CoV-2 and adenovirus co-infection, co-infection was significantly associated with in-hospital mortality compared to SARS-CoV-2 mono-infection (2). Another report demonstrated that, with simultaneous AdV and SARS-CoV-2 infection in vitro and in vivo, AdV infection does not inhibit SARS-CoV-2 replication, and co-infected AdV and SARS-CoV-2 hamsters had more pronounced lung damage and clinical manifestations than mono-infected animals (4). Unfortunately, these reports did not mention any characteristic symptoms of AdV infection.

There have been several case reports of severe pneumonia caused by co-infection with AdV and SARS-CoV-2 but no reports of severe cases with symptoms mainly caused by AdV were identified in our literature search. The most reported COVID-19 symptoms were fatigue (39.2-79%), a fever (61.1-76%), loss of smell/taste (70%), and dry cough (65.2-66%) (6,7). Feikin et al. showed that vaccine efficacy or effectiveness against severe disease was maintained above 70% for up to 6 months after full vaccination (8), and another systematic review showed that vaccine efficacy could be enhanced by a booster (8). The patient in the present case had received his second SARS-CoV-2 vaccination, albeit seven months earlier, which may have contributed to the prevention of severe COVID-19.

In contrast, the present patient's severe and various symptoms may have been caused mainly by AdV infection due to co-infection with AdV and SARS-CoV-2, as severe AdV infection can cause various symptoms, including pharyngo-conjunctivitis, urethritis, and erythema (9). Antigen and PCR tests for AdV, as well as PCR tests for gonorrhea and chlamydia from the urethral swab, were negative. However, given that the AdV antigen test of the throat swab was positive and that there are strains that can cause urethritis, it is possible that his urethritis was caused by severe AdV infection with concomitant co-infection with SARS-CoV-2.

The incidence of conjunctival congestion in COVID-19 was reported to be only 5.0% (n=27/535) (6), and conjunctival congestion occurred in patients with more severe COVID-19 (6). There were no previous reports of COVID-19 urethritis in our literature search. Frequent skin rashes of COVID-19 are macular and papular lesions, livedo reticularis, chilblains, and urticarial lesions (10). However, maculopapular rashes are not specific to COVID-19, as cytotoxic T cells attracted by viral-infected endothelial cells cause rashes (10). This was a limitation associated with the present case, as the local virological test results were insufficient, and the scientific evidence might not be sufficient to support our speculation. Although it was difficult to explain the systemic symptoms mainly by SARS-CoV-2 infection, it was easy to suggest that the various symptoms in the present case may have been caused mainly by AdV infection and may have become severe due to co-infection with SARS-CoV-2. However, in the present case, no family members living in the same household were symptomatic, and the route of the AdV infection could not be identified.

AdV infection is known to be common and has a good prognosis, but this case report demonstrated that co-infection with SARS-CoV-2 could result in severe AdV infection, even in an adult who received a second dose of the SARS-CoV-2 vaccine. In cases of coinfection with SARS-CoV-2, it is necessary to be careful about the risk of worsening symptoms due to other viruses. Research on such interactions, such as the amplification of SARS-CoV-2 and co-infected viruses in organs other than the lungs, is expected to progress over time.

Written consent was obtained from the patient for publication of this case report and accompanying images.

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