Key clinical message
Suspicion threshold for opportunistic coinfections should be lowered in
severe COVID-19. Serum CMV polymerase chain reaction and colonoscopy
should be discussed in presence of persistent digestive disturbances.
Introduction
In severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease
(COVID-19), lymphopenia has been
established as a typical feature and a marker of poor prognosis [1].
Deep immune imbalance and depleted T cells have been reported in
severely ill patients [2-5].
Concerns are rising about COVID-19
associated immunodepression, as series of invasive aspergillosis (IA)
[6-9] have been reported. In one of these reports, up to 35% of
critically ill SARS-CoV-2 infected patients had suspected IA (later
either histologically proven or underpinned by bronchoalveolar fluid or
serum positive galactomannan) [6], whereas the usual overall
incidence of IA in the intensive care unit (ICU) is around 1% [10].
Herein, we report a case of complicated cytomegalovirus (CMV) and
COVID-19 coinfection, in a formally immunocompetent host.
Case presentation
By end of March 2020, a 71-year-old man was admitted to the ICU for
acute respiratory distress syndrome (ARDS). Admission PaO2/FiO2 ratio
was 165 mmHg and Simplified Acute Physiology Score III was 61 (predicted
mortality of 38%). Real-time polymerase chain reaction for SARS-CoV-2
on nasopharyngeal swab was positive.
His medical history was characterized a post-tuberculosis aspergilloma
known since 2016. There was no current medication.
Chest CT-scan displayed ground glass opacities involving over 65% of
the right lung and cavitary tuberculosis sequelae in the left superior
lobe with aspergilloma. A bronchoalveolar lavage fluid analysis revealed
a positive galactomannan (GM) test (value 1.51). Serum GM was negative.
Voriconazole was started on day 5 after admission.
On day 16, ileus was noticed. Abdominal CT-scan showed a right-sided
colitis and ileal distension without obstacle. Persistent anaemia
prompted endoscopic investigations. The colonoscopy performed on day 28
revealed a right-sided colitis with multiples ulcers. CMV colitis was
confirmed by immunoperoxydase staining on colon biopsy. Ganciclovir was
initiated on day 30. Significant rectal bleeding led to caecal artery
embolization.
Serologic tests were positive for past CMV infection and negative for
Human Immunodeficiency Virus. Absolute CD4 cells count was 1368/µL on
day 42, with a CD4/CD8 ratio of 0.5 and normal values for
immunoglobulins and complement. On day 43, the first measured serum CMV
load was 1173 UI/mL.
The patient required 27 days of invasive mechanical ventilation and 9
days of continuous veno-venous hemofiltration. He was discharged from
the ICU on day 32. A control colonoscopy on day 44 showed persisting
signs of right-sided colitis. Ganciclovir was discontinued on day 59.
Discussion
To our knowledge, this is the first description of a CMV end-organ
infection complicating COVID-19 disease in a previously formally
immunocompetent host.
The first CMV and SARS-CoV-2 coinfection was reported in a 92-years-old
Italian woman with diabetes mellitus and hypertension [11]. There
was however no evidence of any end-organ CMV disease. She died 6 days
after admission due to ARDS.
In a systematic review on coinfections among hospitalized COVID-19
patients, viruses were accountable for 3% of the coinfections [12].
CMV was the least frequently encountered virus. CMV infection diagnosis
methods were not reported, nor were severity or end-organ lesions.
CMV colitis is rarely described among immunocompetent patients. Among
1061 colon biopsies in symptomatic patients, CMV polymerase chain
reaction (PCR) was positive in 185 samples. Of those, 15 samples
belonged to 13 immunocompetent hosts and only one of them had compatible
histological findings [13].
CMV is less rare in the ICU. In a meta-analysis involving 2398 patients,
CMV infection or reactivation were found in respectively 27% and 31%
of the patients [14]. The odds ratio for all-cause mortality among
patients with CMV infection was 2.16 compared to control. Interestingly,
patients with sepsis have the highest incidence of CMV infection
[15]. As the inhibition of CMV reactivation requires 10% of all
peripheral CD4+ and CD8+ T cells [16], it is plausible that the
immune dysregulation and the cytokine storm accompanying COVID-19
disease might participate to an increased risk of CMV end-organ disease.
Among severe COVID-19 cases, most had immune dysregulation dominated by
low expression of HLA-DR on CD14 monocytes [17], triggered a.o. by
excessive release of IL-6 and profound lymphopenia. That pattern was
however distinct from the immunoparalysis state reported in bacterial
sepsis or H1N1 influenza severe respiratory failure. Within 15
peripheral blood smears from COVID-19 patients admitted in ICU,
cytological signals of Th2 immune response were found [18].
Several immunoassays studies have demonstrated significantly lower CD3+,
CD4+ and CD8+ counts among severe COVID-19 patients [2-4]. In one of
them [2], median values for CD3, CD4 and CD8 counts among severe
patients were respectively: 305, 184 and 121/µL, suggesting a deep
disturbance of cell-mediated immunity. CD4/CD8 ratio was however not
altered [2,3], unlike in other viral infections such as HIV or CMV.
B and NK cells counts were significantly lower among severely ill
patients in two studies [2,3], yet not in another [5].
A longitudinal study of 40 COVID-19 patients [5] showed a
significant decrease in lymphocytes count from day 7 to 15 after disease
onset, in severe versus mild patients. The lowest CD3+, CD4+ and CD8+
counts were observed at day 4-6.
A review suggested a link between CMV-related immune senescence and the
poor outcome of COVID-19 among older persons [19]. It also suggested
a relationship between the CMV seroprevalence in some areas such as
northern Italy and the higher rates of COVID-19 mortality in those
populations. Those links remain to be demonstrated.
Ultimately, we consider that our patient’s CMV colitis was likely
triggered by his immune dysregulation due to severe COVID-19.
Conclusion
To our knowledge, this is the first described case of CMV end-organ
disease concomitant to COVID-19 in an immunocompetent host.
Studies show that critically ill COVID-19 patients have an imbalanced
immune response with deep T lymphopenia that may render them more
susceptible to various infections.
Opportunistic infections are not
systematically sought for in immunocompetent people. A part of the high
mortality related to COVID-19 might be imputable to such undiagnosed
diseases. Evidence is growing for IA coinfections, but other diseases
might be underestimated, such as CMV reactivations.
Suspicion threshold for opportunistic diseases should be lowered when
managing critically ill COVID-19 cases. Serum CMV PCR and endoscopic
exploration with biopsy should be discussed in presence of persistent
and unexplained digestive disturbances.
Further large-scale studies are warranted to investigate whether severe
COVID-19 patients are prone to opportunistic infections.