Table 2.
Factors related to clinical features and outcomes of COVID-19 and Herpesviridae co-infection or reactivation.
| Author, year | Virus | Reactivation/co-infection | Significantly associated parameters |
Outcome measures | ||||
|---|---|---|---|---|---|---|---|---|
| Clinical feature (%) | Laboratory findings | Percentage of steroid intake with duration and dosage | Outcome | |||||
| Meshram et al., 2022 [24] | CMV | Co-infection after post renal transplantation | Acute Kidney Injury (66), AKI requiring dialysis (11), Oliguria AKI (55), Non oliguric AKI (11) |
Low lymphocyte count, increased D-dimer, CRP, LDH, IL-6, Ferritin | 14 (78%) patients | Recovered: n = 14 (78%), Dead: n = 4 (22%), Days of hospitalization: 12.5 (14-11) |
Not reported | Not reported |
| Almutairi et al., 2022 [23] | Herpes Zoster virus | Concurrent or may be reactivation | Pain (66.67), Thoracic segment (41.67), Cervical (8.33), Cranial (16.67) Lumbar (25), Sacral region (8.33) involvement, secondary bacterial infection (16.67), severe ulceration (8.33) | Leucopenia, lymphopenia, decreased Hemoglobin, raised ESR, CRP, IL-6, AST, ALT | 2 (16%) patients | Hospitalization 2 (16.67%); Oxygen support: 1 (8.67%) |
Not reported | Not reported |
| Simonnet et al., 2021 [25] | EBV, CMV, HHV-6 | reactivation | Features of single, double and triple viremia | Not reported | 30 (88%) patients | ICU discharge: 28 (82%); Death: 6 (18%) (EBV reactivation- 3(50%); EBV + CMV reactivation- 1(17%)); Longer median ICU length of stay: EBV vs No EBV: 15 days vs 8 days |
Longer median ICU length of stay: EBV vs No EBV: <0.05 | Not reported |
| Chen et al., 2021 [35] | EBV | coinfection | fever (61.2), dry cough (52.2), fatigue (46.3), myalgia (26.9), anorexia (23.9) | Raised CRP, LDH level, AST | VCA IgM (+) vs VCA IgM (−): 22 (59.5%) vs 10 (33.3%) | All were discharged | EBV/SARS CoV-2 co-infection vs SARS C0V-2 infection alone: C/F: Fever: 0.03; Inflammatory marker: CRP: 0.02; Corticosteroid use: 0.03 |
EBV/SARS CoV-2 co-infection vs SARS C0V-2 infection alone: C/F: Fever: 3.09 (1.11–8.56) |
| Lino et al., 2021 [26] | HHV-6B | coinfection | fever, cough, throat pain, sneezing, loss of taste, diarrhea, abdominal pain | Not reported | yes | ICU requirement: 9 (69.3); Mortality: 4 (30.7) (Not significant when compared with w/out co-infection group) |
W/out co-infection vs W co-infection: Therapeutic immunosuppresion: 0.01 | Not reported |
| Yamamoto et al., 2021 [13] | CMV | Coinfection/reactivation | Possible CMV DNAemia, gastrointestinal symptoms and pneumonia | D-dimer level | Corticosteroid pulse therapy before ICU admission: Pt with CMV vs w/out CMV: 5/15 (33.3%) vs 8/44 (18.2%); Systemic corticosteroid therapy, days, after ICU admission: Pt with CMV vs W/out CMV: 30 (20–41) vs 13 (11–15) Dexamethasone 6 mg Once daily for 10 days or ICU discharge, If > 10 days, still not extubated, ≤6 mg dexa once dailly until extubation or death. tapering to 1–3 mg once daily |
ICU discharge: 11 (73.4%); Death: 4 (26.6%); |
Characteristics of Pt with CMV and w/out CMV:
|
Risk factor analysis for CMV infection during the ICU stay:
|
| Giacobbe DR., 2022 [36] | HSV-1 | Reactivation | Not reported | Not reported | yes 38 (93%) of total patient population | Crude 30 day mortality: With HSV-1 reactivation vs whole study population: 3/12 (25%) vs 13/41 (32%) |
Not reported | Not reported |
| Fuest et al., 2022 [11] | HSV-1, CMV (No CMV was found in the cohort) | reactivation | Not reported | Not reported | yes 39 (64%) with HSV infection, 49 (67%) with no infection | ICU mortality: HSV-1 (+) vs hSV-1 (−): 35 (57.4%) vs 33 (45.2%) ∗Not significantly associated |
Univariates analysis: HSV vs Non HSV:
Multivariate analysis in HSV positive group as influencing factor for HSV infection:
|
Multivariate analysis in HSV positive group:
|
| Xie et al., 2021 [12] | EBV | reactivation | Tachypnea: 15 (88.2%) Respiratory failure: 13 (76.5) ARDS: 15 (88.2%) | Hyponatraemia: Lymphocyte count, Albumin, D-dimer, Calcium, CRP | Yes Glucocorticoids 1–2 mg/kg for 5–7 days | Mortality: EBV (+)5/17 (29.4%) | EBV vs Non-EBV: C/F: Tachypnea: <0.001; Respiratory failure: 0.001; ARDS: <0.001; Laboratory Ix: Hyponatraemia: <0.001 Lymphocyte count: 0.0002 (Inverse); Albumin: 0.03 (Inverse); D-dimer: <0.0001; Calcium: <0.001; CRP: 0.004 Prognosis: 28-day mortality: 0.0046: 14-day mortality: 0.0046 Multivariate analysis: Better prognosis in non-EBV group: <0.001 |
Multivariate analysis: Better prognosis in non-EBV group: HR: 0.56 (0.116–2.689) |
| Abadias-Grando et al., 2021 [27] | HHV-6 | reactivation | Cutaneous manifestation: maculopapular, ptyriaisis like, perniosis like, vesicular, multiform, seborrhoeic dematitis, urticarial | Not reported | Not reported | Not reported | Not reported | Not reported |
| Niitsu et al., 2021 [37] | CMV | reactivation | CMV antigenaemia; CMV pneumonia |
CMV (+) vs CMV (−): Lymphocyte on ICU admission: 393/μl vs 525/ul |
yes 6 (100%) in CMV group, 20 (100%) in non CMV group | 2 (33.33%) were dead | CMV vs Non-CMV group: Duration of mechanical ventilation, days: 0.010 Bacterial infection: 0.018 Fungal infection: 0.013 Death: 0.046 |
Not reported |
| Navaro Bielsa, 2021 [28] | HHV-6 | Both coinfection and reactivation | Cutaneous manifestation macolopapular eruptions: 24 (38.1); erythema with vesicles or pustules (pseudo-chilblain): 13 (20.6); Vesicular eruption: 8 (12.7); urticarial leisons: 6(9.5); Livedo or necrosis: 5(7.9) | Not reported | Yes Topical and oral corticosteroid |
all were recovered | Not reported | Not reported |
| Balc'h et al., 2020 [29] | HSV, CMV | reactivation | Not reported | Not reported | yes 16 (80%) in no reactivation group and 16 (89%) in reactivation group | 2 (11%) were dead but not statistically relevant when compared with non reactivation group | No-reactivation vs Reactivation: Duration of MV: 0.0001; Ventilator-free days at D28: 0.0008 (−); PaO2: FiO2:(D7): 0.04 (Inverse); PaO2: FiO2:(D14): 0.01 (−); ICU length of stay: 0.0001 |
Not reported |
| Franchesch et al., 2021 [34] | HSV-1 | reactivation | 2 hepatitis (9.5%), 5 herpes labialis (23.8%), 4 pneumonia (19%), 3 gingivostomatitis (14.3%) and 1 encephalitis (4.8%) | Higher level of LDH | yes 16 (76%) in HSV 1 positive, 24 (49%) in negative Methylpredinosolone IV with an initial bolus of 0.5 mg/kg followed by 0.5 mg/kg 4 times daily for 7 days, 0.5 mg/kg 3times daily day 8–10, 0.5 mg/kg 2 times daily day 11–12, 0.5 mg/kg once daily for day 13 and 14. For failed Tocilizumab rx, bouls dose 1g IV for 3 consecutive days |
Invasive mechanical ventilation: 12 (57.1%) Death: 6 (28.6%) |
HSV 1 positive (re-activation) vs negative in COVID pt: C/F: Systolic BP: 0.027 Lab: LDH: 0.022 Intervention: Steroid use: 0.036 Outcome: IMV: 0.005 After logistic regression: Steroids use: Any dose vs No: 0.016 Low dose vs No: 0.027 High dose vs No: 0.043 |
HSV 1 positive (re-activation) vs negative in COVID pt: After logistic regression: Steroids use: Any dose vs No: 5.13 (1.36, 19.32) Low dose vs No: 4.80 (1.20, 19.26) High dose vs No: 6.16 (1.06, 35.74) |
| Reizine et al., 2021 [30] | HSV-1, CMV | reactivation | Not reported | Not reported | yes 85 (95%) in non reactivation, 29 (87%) in reactivation | 1 was dead | No viral reactivation vs Viral reactivation: C/F: Obesity: <0.001; HTN: 0.042; Lab: Duration of lymphopenia (days): 0.001; Clinical course: Duration of (+) resp. SARS CoV-2 RT PCR (days): 0.013; Outcome: Ventilator associated pneumonia: 0.03; Herpesviridae res reactivation: <0.001; Duration of mechanical ventilation (days): 0.018; Length of ICUU stay (days): 0.005 |
Not reported |
| Saade et al., 2021 [32] | HSV, EBV, CMV | reactivation | esophagitis, cutaneous-mucous manifestations | Higher leukocyte count | yes 6 (16%) in non reactivation, 27 (43%) in reactivation group | 23 were dead but statistically proved that it was not realted to viral reactivation. | No Reactivation vs reactivation: Characteristics/Immunosuppressive cond: Valaciclovir prophylaxis: 0.05; Hematopoietic cell transplantation: 0.05; Lab: Leukocytosis on ICU admission: 0.02; Therapeutics: dexamethason: 0.01; Infectious event: 0.04; Bacterial event: 0.02; Pneumonia: 0.05; ICU stay: 0.03 After adjustment using Fine and Gray model: Preexisting hematological malignancy: 0.02; Solid organ transplantation: 0.02 |
After adjustment using Fine and Gray model: Preexisting hematological malignancy: 0.31 (0.11–0.85); Solid organ transplantation: 2.09 (1.13–3.87) |
| Meyer et al., 2021 [38] | HSV-1 | reactivation | fever | Higher level of CRP and LDH | yes 86 (56%) in non reactivation, 22 (55%) in reactivation | Death in ICU: 21 (52.5); Death at day 60: 23 (57.5); HAP/VAP: 33(82.5); ICU-BSI: 18 (45); IMV/ECMO: 35 (87.5) |
Without reactivation vs Reactivation: On ICU admission: C/F: Max body temp: 0.029; Lab: CRP: 0.001; LDH: 0.019; Intervention: MV: 0.009; Initial use of corticosteroid: 0.016; Outcomes: Length of stay in ICU: <0.001; Death in ICU: 0.02; Death at day 60: 0.014; HAP/VAP: <0.001; ICU-BSI: 0.001; IMV/ECMO: <0.001 After adjustment, in multivariable Cox models, increased risk of mortality: 0.01; After adjustment for mortality factors and using acyclovir as a time-dependent covariate, in Cox model, increased risk of mortality at day 60: <0.001; Multivariable specific cause models showed an increased risk of HAP/VAP: 0.037; In blood samples, multivariable cause-specific models, association between HSV-1 reactivation and HAP/VAP: 0.027 |
After adjustment, in multivariable Cox models, increased risk of mortality in all sample: HR 2.05 (1.16–3.62); After adjustment, in multivariable Cox models, increased risk of mortality in blood sample: HR 2.24 (1.23–4.08) After adjustment for mortality factors and using acyclovir as a time-dependent covariate, in Cox model increased risk of mortality at day 60: HR 4.37, 95% CI 2.12–9.02; 0.059). Multivariable specific cause models showed an increased risk of HAP/VAP: csHR 2.38, 95% CI 1.06–5.39; In blood samples, multivariable cause-specific models, association between HSV-1 reactivation and HAP/VAP: HR 2.62; 95% CI 1.12–6.12 |
| Gold et al., 2021 [31] | EBV | reactivation | Fatigue, insomnia, headache, myalgia, confusion, tinitus, hearing loss, skin rashes, covid toes | Not reported | Not reported | Not reported | Long term COVID vs Long term control group; Difference in the fraction of EBV reactivation: <0.001; Short-term COVID vs short-term control group: 0.05; Relationship of EBV EA-D IgG with the number of reported long COVID symptoms: p < 0.001 |
Relationship of EBV EA-D IgG with the number of reported long COVID symptoms: r = 0.34 |
| Meng et al., 2022 [33] | EBV | reactivation | Not reported | Lower Hb level, Higher D-dimer level and bilirubin level. | Not reported | Patients with EBV reactivation have statistically nonsignificant higher mortality rate: 12 [22%] vs. 18 [11%], | EBV serology, Non-survivor vs Survivor: EA-IgG: 0.05; Lab: with reactivation vs w/out reactivation: Hb: 0.007; D-dimer: 0.03; total bilirubin: 0.006; After intervention with Ganciclovir: Lab: Hb level: <0.001; prealbumin level: 0.02; Outcome: Effects on 28 days survival rate: 0.01 (−); Length of stay: 0.006 |
EBV serology, Non-survivor vs Survivor: EA-IgG: −0.00005 (−3.10, 0.00); After intervention with Ganciclovir: Outcome: Effects on 28 days survival rate: 0.98 (0.95, 1.00) |