Online tables:
Table 1A – Non-interventional, diagnosing oral herpes simplex virus (HSV) infection based on clinical and laboratory criteria
Authors / Cancer treatment modality / Population included / Outcome / Outcome measure / Outcome type / Timing of assessment / Frequency / Microbiology test collection / Additional data – lab. test / Additional data – clinical assessment1 / Redding et al.1990 [1] / RT / All patients (regardless of HSV serology) / Incidence of HSV infection / Presence of viral infection based on a combination of clinical and lab findings, per patient / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / “Periodically” / From oral lesions / Culture
Incidence of HSV infection / Presence of viral infection based on a combination of clinical and lab findings, per episode / Yes/No
2 / Bergmann et al. 1990 [2] / CT / All patients with fever (regardless of HSV serology) / Incidence of HSV infection / Presence of viral infection based on a combination of clinical and culture findings, in patients with fever / Yes/No / Fever for more than 2 hours / Daily, for 7 days. / From oral lesions in the “oral lesion” group, and regardless of oral lesions in the “non-oral lesion” group / Culture, HSV Ab titer
Culture by gargle of culture medium and by a swab from the oral lesion.
HSV Ab titer – increased/unchanged after dat 1 / Comparison of 2 groups: “with oral lesion”, “without oral lesion”
Suspicious lesion were cultured too
Incidence of HSV infections / Presence of viral infection based on a combination of clinical and titre findings, in patients with fever / Yes/No
Anatomic distribution / Anatomic site of oral lesion with positive HSV culture. / Categorical
3 / Lloid et al. 1994[3] / Patients with positive CMV serology or CMV positive blood product / Diagnosis of CMV / Presence of viral infection based on a combination of clinical and lab findings and response to anti-viral treatment / Yes/No / At the appearance of oral lesions / Not relevent / From oral lesions / Biopsy: histology; CMV immunohistochemistry to detect viral antigens; CMV in-situ hybridization; culture.
4 / Chandrasekar et al. 2001 [4] / HSCT / All patients (regardless of HSV serology) / Incidence of HSV infection / Clinical signs / Yes/No / Started at the beginning of cancer treatment (First 2 weeks after HSCT) / Daily / From oral lesions / Culture / HSCT for breast cancer
Documented clinically without culture confirmation
Incidence of HSV infection, per patient / Clinical signs / Yes/No
5 / Gomez et al.2001[5] / HSCT / All patients / Mortality / Alive / Yes/No / After completion of treatment / Monthly / From oral lesions / Exfoliative cytology (n=11)
PCR (n=3)
6 / Sepulveda et al. 2005[6] / CT / Not specified / Number of lesions / One/Multiple / Dichotomic / At the appearance of oral lesions / Once per chemotherapy cycle / From oral lesions / PCR
Size of lesions / 1-5mm
5-10mm
10-15mm / Catagorical
Clinical signs / Halo / Yes/No
Clinical signs / Regular edge / Yes/No
Clinical signs Clinical signs / Exudate
1. Hemmorhagic
2. Fibrinous
3. Other (Serous or necrotic exudate) / Categorical
Anatomic distribution / Anatomic site
7 / Djuric et al. 2009 [7] / CT / All patients (regardless of HSV serology) / Incidence of HSV infection, per patient / Presence of viral infection based on a combination of clinical and lab findings / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / Once per chemotherapy cycle / From oral lesions in the “oral lesion” group, and regardless of oral lesions in the “non-oral lesion” group / Culture, HSV Ab titer, typing for HSV-1/2, identification of HSV Ab, identification of HSV genome / Study aimed to compare various diagnostic methods for HSV.
Incidence of herpes labialis / Presence of viral infection based on a combination of clinical and lab findings / Yes/No
Severity of oral lesions – / WHO scale for mucositis
1. Mild oral pain, erythema
2. Moderate oral pain, edema or
ulcer, but could eat
3. Severe pain and ulceration, could not eat
Intractable pain, required parentral or entral support / Categorical
8 / Chen et al. 2011 [8] / CT / Patients with oral mucositis / Incidence for HSV infection, per episode / Presence of viral infection based on a combination of clinical and lab findings / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions (retrospective study) / Following chemotherapy course with oral mucositis (retrospective study) / From oral lesions / Culture
Parental nutrition / Need for parentral nutrition / Yes/No
RT Radiation therapy; CT chemotherapy; Ab antibody; CMV cytomegalovirus; HSCT hematopoietic stem cell transplantation; WHO World Health Organization.
Table 2A – Non-interventional, diagnosing oral herpes simplex virus (HSV) infection based on laboratory criteria only
Authors / Cancer treatment modality / Population included / Outcome / Outcome measure / Outcome type / Timing of assessment / Frequency / Microbiology test collection / Additional data –assessment1 / Beattie et al. 1989 [9] / CT / Neutropenic patients with oral ulcers (regardless of HSV serology) / Incidence of HSV infection / Positive culture from ulcer / Yes/No / At the appearance of oral lesions / Not specified / From oral lesions
2 / Schubert 1990 [10] / HSCT / All patients (regardless of HSV serology) / Incidence of HSV infection / Positive culture / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / Every other week / Regardless of the presence of oral lesions / Suspicious lesions were cultured too
This clinical measure was reported but was not required for diagnosis of HSV infection.
Time of HSV infection / Time relative to days of transplant / Serial
Anatomic distribution / Anatomic site of lesion: lips, mouth, and/or throat / Categorical / Started at the beginning of cancer treatment, regardless of the presence of oral lesions.
3 / Epstein et al. 2002 [11] / RT / All patients (regardless of HSV serology) / Incidence of HSV infection / Positive culture / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / Weekly / Regardless of the presence of oral lesions
4 / Guimaraes et al.[12] / HSCT / All patients (regardless of HSV serology) / Viral shedding at 3 time points: Before allo. HSCT, at 100 days post HSCT and 1 year post HSCT / Positive HSV PCR / Yes/No / Before the beginning of cancer treatment, regardless of the presence of oral lesions. / Not appplicable / Regardless of the presence of oral lesions / Cross sectional study; matched with a healthy control group
Mortality / Death by day 100 after allogenic transplant / Yes/No
5 / Ruping et al. 2011 [13] / CT or HSCT / All patients (regardless of HSV serology) / Incidence of HSV infection / Positive culture / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / Taken on days -6,0,6,14,100 / Regardless of the presence of oral lesions / OAG – 8 item instrument evaluating voice, swallowing, lips, tounge, saliva, mucosa, gingiva, teeth. Score ranges 8-24;
moderate – 9-16;
severe – 17-24
Incidence of HSV infection / Positive HSV -PCR / Yes/No
Incidence of HSV infection / Positive HSV-IgM / Yes/No
Severeity of mucositis / Oral assessment guide (OAG) / Categoircal
Incidence of viral infection / Positive PCR or cell culture for VZV, CMV, HPV, Adenovirus. Parainfluenza virus, Influenza virus / Yes/No
CT chemotherapy; HSCT hematopoietic stem cell transplantation; RT Radiation therapy; PCR polymerase chain reaction; OAG oral assessment guide; VZV varicella zoster virus; CMV cytomegalovirus; HPV human papilloma virus.
Table 3A – Non-interventional, diagnosing oral herpes simplex virus (HSV) infection based on clinical criteria only
Authors / Cancer treatment modality / Population included / Outcome / Outcome measure / Outcome type / Timing of assessment / Frequency / Microbiology test collection / Additional data – lab. test / Additional data – clinical assessment1 / Dreizen et al. 1983 [14] / CT / Patients with oral lesions / Incidence of HSV infection, per patient / Clinical signs / Yes/No / At the appearance of oral lesions (retrospective study) / Not specified / From oral lesions / Culture / Herpetic lesions were diagnosed by clinical criteria. For questionable lesions they used culture.
2 / Ramirez-Amador et al. 1996 [15] / CT / All patients (regardless of HSV serology) / Incidence of HSV / Clinical signs calculated as lesions per 100 patient week. / Serial / At the appearance of oral lesions / Weekly, up to 8 weeks.
Time of HSV infection / Week of detection / Serial (week number)
Healing / Duration of HSV infection / Serial (weeks)
CT chemotherapy; RT Radiation therapy; RTOG Radiation Therapy Oncology Group; EORTC European Organisation for Research and Treatment of Cancer.
Table 4A – Interventional prevention studies, diagnosing oral herpes simplex virus (HSV) infection based on clinical and laboratory criteria
Authors / Cancer treatment modality / Population included / Outcome / Outcome measure / Outcome type / Timing of assessment / Frequency / Microbiology test collection / Additional data – lab. test / Virus tested1 / Saral et al. 1981[16] / HSCT / Patients with positive HSV serology / Incidence of HSV infection, per patient / Presence of viral infection based on a combination of clinical and lab findings / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / Daily until day 30, twice weekly until day 80 / Regardless of the presence of oral lesions / Culture (gargle) - HSV and CMV; Titers of anti HSV and anti CMV / HSV, CMV
2 / Hann et al. 1983[17] / HSCT / Patients with positive HSV serology / Incidence of HSV infection, per patient / Presence of viral infection based on a combination of clinical and lab findings / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / Twice weekly / Regardless of the presence of oral lesions / Urine spemines, throat and perio-oral swabs taken twice weekly; Suspicious lesion were cultured daily / HSV
3 / Saral et al. 1983[18] / CT / Patients with positive HSV serology / Incidence of HSV infection, per patient / Presence of viral infection based on a combination of clinical and lab findings / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / Daily / Regardless of the presence of oral lesions / Culture (gargle) - HSV;
Suspicious lesion were cultured too / HSV
4 / Barrett et al. 1986 [19] / HSCT / All patients (regardless of HSV serology) / Incidence of HSV infection, per patient / Presence of viral infection based on a combination of clinical and lab findings, or/and response to anti-viral treatment / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / Daily / From oral lesions / Culture and exfoliative cytology / HSV
Incidence of HSV infection, per episode / Presence of viral infection based on a combination of clinical and lab findings, or/and response to anti-viral treatment / Yes/No
Mucosal involvement / Type of mucosa involved: keratinized / non-keratinized / Categorical
Recurrence of infection following cessation of anti-viral treatment, per patient / Number of patients that relapsed / Serial
Recurrence of infection following cessation of anti-viral treatment, per episode / Number of episodes of relapse / Serial
Occurance of toxicity / Not specified / Yes/No
5 / Shepp et al. 1987 [20] / HSCT / Patients with positive HSV serology / Incidence of HSV infection, per patient / Presence of viral infection based on a combination of clinical and lab findings / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / More than once a week, but not daily. / Regardless of the presence of oral lesions / Culture / HSV
Type of infection –
HSV-1 / HSV-2 / Categorical
Severity of the infection –
degree of erythema (none, mild, moderate, severe). / Categorical
Necessity for acyclovir treatment / Suspected or proved HSV infection / Yes/No
Time to 1st positive HSV culture during prophylaxis / Serial (week)
6 / Engelhard et al. 1988 [21] / HSCT / Patients with positive HSV serology / Incidence of HSV infection, per patient / Presence of HSV infection based on a combination of clinical and lab findings
Diagnosis of VZV infection was based on clinical findings only. / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / Daily when hospitalized, and weekly after discharge. / Regardless of the presence of oral lesions / Serology, culture-HSV. / HSV, VZV
Occurance of VZV infection / Infection rate relative to the time of BMT / Categorical
Occurance of toxicity / Not specified / Yes/No
Time to engraftment / Days post- BMT / Serial
7 / Epstein et al. 1990 [22] / RT, CT or both / All patients (regardless of HSV serology) / Incidence of HSV infection, per patient / Presence of viral infection based on a combination of clinical and lab findings / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / not specified / From oral lesions / Culture, cytology, HSV Ab titer. / HSV
Degree of erythema:
none, mild, moderate, severe / Categorical
Response to acyclovir treatment / Clinical appearance / Yes/No
8 / Warkentin et al. 2002 [23] / CT or HSCT / Patients with positive HSV serology / Prevalence for HSV infection, per patient (i.e. success of various anti-viral prophylaxis protocols) / Presence of viral infection based on a combination of clinical and lab findings / Yes/No / Started during cancer treatment, regardless of the presence of oral lesions. / daily (oral examination), weekly or more frequent of lesion was present (culture) / Regardless of the presence of oral lesions / Culture-HSV, serology CMV / HSV and CMV
Comparison of antiviral drugs/ doses
Incidence of CMV infection, per patient / Presence of viral infection based on a combination of clinical and lab findings / Yes/No
Sensitivity to acyclovir / ID 50 The concentration of acyclovir reducing plaque formation by 50 % / Serial
Incidence of VZV infection, per patient / Presence of viral infection based on a combination of clinical and lab findings / Yes/No
Oral ulceration / Bearman Mucositis Score
1. No
2. Pain and oral ulceration, no IV narcotic drug
3. Pain and oral ulceration, with IV narcotic drug
4. Severe ulcer and/or mucositis requireing preventive intubation or resulting in documented aspiration pneumonia with or without intubation
5. fatal toxicity / Categorical
Time to development of viral infection / Duration of anti-viral prophylaxis / Serial (days)
Incidence of adverse effects / System involved / Yes/No
Drug safety according to published criteria / Nature, likelihood association to study drug, and severity / Categorical
9 / Eisen et al. 2003 [24] / HSCT / Patients with positive HSV serology / Incidence for HSV infection, per patient / Presence of viral infection based on a combination of clinical and lab findings, unless clinical presentation strongly suggested of HSV infection / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / Weekly / Regardless of the presence of oral lesions / Culture, typing HSV-1/2 / HSV
Comparison of antiviral drugs/ doses
Drug safety according to published criteria / Organ toxicity, likelihood association to study drug, and severity / Categorical
Tolerance / Number of prophylaxis days treated / Serial
Tolerance / Number of doses / Serial
Compliance with therapy / % of patients completed anti-viral therapy without need for IV acyclovir / Serial
10 / Orlowski et al. 2004[25] / CT / Patients with positive HSV serology
Patients with unknown serology at the time of admission / Effectiveness of valacyclovir in preventing reactivation of HSV based on the fullfillment of the following criteria / findings.
1. Development of an active herpatic infection (ombination of clinical and lab)
2. Recovery of absolute neutrophile count of 250 (and of time period of risk)
3. Suspected episode of thrombotic thrombocytopenic purpurea(TTP) or hemolytic-uremic syndrome / Yes/No / Started at the beginning of cancer treatment, regardless of the presence of oral lesions. / More than once a week, but not daily. / Regardless of the presence of oral lesions / Culture / HSV
Toxicity / Grade 3 according to NCI-CTC / Categorical
HSCT hematopoietic stem cell transplantation; CMV cytomegalovirus; CT chemotherapy; VZV varicella zoster virus; BMT bone marrow transplantation; RT radiation therapy; IV intravenous; NCI-CTC National Cancer Institute-Common Toxicity Criteria.