Table 1.
Laboratory-based Biomarkers
| Laboratory Parameters | Tissue Tested | Significant Results | Totality of the Evidence | Studies |
|---|---|---|---|---|
| I. INFECTIVE | ||||
| Antistreptolysin O antibody (ASO) | Serum | Positive in PANS/PANDAS (>250 IU) | *** | Pavone et al (2004)167 [CCS]; Kurlan et al (2008)168 [OS]; Morris et al (2009)169 [OS]; Murphy et al (2012)34 [CSS]; Stagi et al (2014)170 [CCS]; Cox et al (2015)87 [OS]; Stagi et al (2018)171 [CSS]; Chain et al (2020)78 [CSS]; Murphy and Pichichero (2002)172 [OS]; Gamucci et al (2019)18 [OS]; Prato et al (2021)172 [SR]. |
| Antistreptolysin O antibody (ASO) | Serum | Negative in PANS (<250 IU) | *** | Luo et al (2004)173 [OS]; Bernstein et al (2010)174 [CCS]; Morris-Berry et al (2013)175 [OS]; Murphy et al (2013)176 [OS]; Gagliano et al (2020)10 [OS]; Gagliano et al (2021)118 [CSS]; Prato et al (2021)172 [SR]. |
| Nasopharyngeal culture for Group A beta-hemolytic streptococcus (GABHS) | Throat | Positive in PANS/PANDAS | *** | Murphy et al (2012)34 [CSS]; Swedo et al (1998)11 [CSS]; Lepri et al (2019)67 [CCS]; Leckman et al (2011)173 [CSS]; Orefici et al (2016)177 [SR]; Bryńska et al (2004)178 [SR], Gagliano et al (2020)10 [OS]; Gamucci et al (2019)18 [OS]; Calaprice et al (2017)13 [CCS]. |
| Nasopharyngeal culture for other bacteria (Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae Pseudomonas aeruginosa) | Throat | Positive in PANS | ** | Gagliano et al (2020)10 [OS]; Prato et al (2021)172 [SR]. |
| IgG and/or IgM Antibodies against different germs (AntiMycoplasma pneumoniae, Chlamydia pneumoniae, Epstein–Barr virus, Borrelia Burgdorferi, and Herpes Simplex Virus –HSV- Type 1) | Blood | Positive in PANS | *** | Chang et al (2015)15 [GL]; Murphy et al (2014)179 [SR]; Hansen et al (2021)180 [SR]; Perrin et al (2004)181 [OS]; Lepri et al (2019)67 [CCS]; Gagliano et al (2020)10 [OS]; Murphy and Pichichero (2002)172[OS]; Esposito et al (2014)182 [SR]; Prato et al (2021)172 [SR]. |
| CSF | Negative in PANS | * | Gamucci et al (2019)18 [OS]. | |
| II. IMMUNE/AUTOIMMUNE | ||||
| Thyroid tests | ||||
| Antithyroid antibodies (Thyroid Stimulating Hormone Receptor Antibody [anti-TSH receptor] Anti-thyroid peroxidase [antiTPO], Thyroglobulin antibodies, TSH receptor antibodies [anti-TRAbs]) |
Blood Blood-serum Blood Blood Blood-serum |
Positive in PANS/PANDAS | *** | Stagi et al (2014)169 [CCS]; Frankovich et al (2015)2 [CCS]; Gromark et al (2019)7 [OS]; Gagliano et al (2020)10 [OS]; Gromark et al (2021)183 [OS]; Gamucci et al (2019)18 [OS]; Prato et al (2021)172 [SR]. |
| Celiac tests | ||||
| Anti-gliadin, Anti-endomysium, Anti-tissue-translglutaminase, |
Serum Serum Serum |
Positive in PANS | ** | Stagi et al (2014)169 [CCS]; Frankovich et al (2015)2 [CCS]; Gromark et al (2019)7 [OS]; Gromark et al (2021)183 [OS]. |
| Organ- and nonorgan-specific autoantibodies | ||||
| Antinuclear antibodies (ANAs) anti-DNasi, anti-smooth muscle, anti-extractable nuclear antigens, anti-phospholipid, lupus-like anticoagulant, Anti-A carbohydrate (anti-ACHO) antibody |
Serum | Positive in PANS/PANDAS | *** | Chain et al (2020)78 [CSS]; Stagi et al (2014)169 [CCS]; Williams et al (2016)115 [RCT]; Gromark et al (2019)7 [OS]; Murphy et al (2012)34 [CSS]; Murphy et al (2013)176 [OS]; Gagliano et al (2020)10 [OS]; Lepri et al (2019)67 [CCS]; Gromark et al (2021)183 [OS]; Frankovich et al (2015)2 [CCS]; Gamucci et al (2019)18 [OS]. |
| Antineural antibodies | ||||
| Dopamine receptors D1 and D2 antibodies lysoganglioside-GM1 (lyso-GM1) antibodies calcium calmodulin dependent kinase II activity (CaMKII-activity) antibodies β-tubulin antibodies |
Serum Serum |
Elevated in PANS | *** | Pavone et al (2004)167 [CCS]; Cox et al (2015)87 [OS]; Morris-Berry et al (2013)175 [OS]; Chain et al (2020)78 [CSS]; Stagi et al (2014)169 [CCS]; Kirvan et al (2006)46 [CCS]; Cunningham et al (2014)184 [SR]; Shimasaki et al (2020)79 [CSS]; Singer et al (2015)185,186 [CCS]; Hesselmark et al (2017)82 [CCS]; Xu et al (2021)22 [CCS]. |
| (CaMKII-activity) antibodies | CSF | Positive PANS/PANDAS | * | Kirvan et al (2006)46 [CCS]; Shimasaki et al (2020)79 [CSS]. |
| Neuronal encephalitis spectrum antibodies | CSF | Negative in PANDAS Negative in PANS |
* * |
Chain et al (2020)78 [CSS]; Gamucci et al (2019)18 [OS]. |
| III. INFLAMMATORY | ||||
| Histone antibodies | Blood | Positive in PANS/PANDAS | * | Frankovich et al (2015)2 [CCS]; Chang et al (2015)15[GL]; Prato et al (2021)172 [SR]. |
| Lymphocyte subset (T, B, natural killer [NK] cells) | Blood | Positive in PANS/PANDAS | * | Leckman et al (2011)173 [CSS]; Gilbert et al (2019)187 [SR]. |
| D8/17-reactive cells | Blood | Positive in PANS/PANDAS | ** | Swedo et al (1998)11 [CSS]; Luo et al (2004)173 [OS]; Sokol et al (2002)188 [CCS]; Prato et al (2021)172 [SR]. |
| Erythrocyte sedimentation rate (ESR) | Blood | Increased in PANS/PANDAS | ** | Frankovich et al (2015)2 [CCS]; Murphy et al (2012)34 [CSS]; Murphy et al (2013)176 [OS]; Gromark et al (2019)7 [OS]; Gromark et al (2021)183 [OS]. |
| C-reactive protein (CRP) | Blood | Increased in PANS/PANDAS | *** | Gagliano et al (2020)10 [OS]; Murphy et al (2012)34 [CSS], Murphy et al (2013)176 [OS]; Frankovich et al (2015)2 [CCS]; Gromark et al (2019)7 [OS]; Gromark et al (2021)183 [OS], Chang et al (2015)15 [GL], Gamucci et al (2019)18 [OS]. |
| Neuron-specific Enolase (NSE) | Serum | Elevated in PANS | ** | Gagliano et al (2021)118 [CSS]; |
| Serum amyloid A (SAA) | Serum | Frankovich et al (2015)2 [CCS]; | ||
| Complement activation | Blood | Stagi et al (2014)169 [CCS]; Prato et al (2021)172 [SR]. | ||
| IgG, IgA, IgM | ||||
| IL-1- β, IL1-ra, IL-2, IL-6, IL8, IL-10, IL-17A, TNF- α, IL-12, IL-12p70, CD-14, SGP130, IL-GR | Serum | Elevated in PANS | ** | Frankovich et al (2015)2 [CCS]; Murphy et al (2012)34 [CSS]; Murphy et al (2013)176 [OS]; Gromark et al (2019)7 [OS]; Gromark et al (2021)183 [OS]. |
| Granulocyte-macrophage colony-stimulating factor (GM-CSF) Cytokines |
Serum CSF Serum |
Elevated in PANS Normal in PANS Increased in PANS |
* * * |
Rodriguez et al (2017)189 [CCS]; Gamucci et al (2019)18 [OS]; Parker-Athill et al (2015);190 Rodriguez et al (2017)189 [CCS] |
| IV. GENERAL HEALTH PARAMETERS | ||||
| Complete blood count (CBC) | Blood | Alterated in PANS/PANDAS | * | Leckman et al (2011)173 [CSS]; Stagi et al (2014)169 [CCS]. |
| Ferritin | Serum | Reduced in PANS/PANDAS | ** | Gromark et al (2019)7 [OS]; Gromark et al (2021)183[OS]; Chan et al (2021)191 [CSS]; Prato et al (2021)172 [SR]. |
| Iron | Serum | Reduced in PANS/PANDAS | * | Chang et al (2015)15[GL]; Chan et al (2021)191 [CSS]; Prato et al (2021)172 [SR]. |
| Vitamin D | Blood | Reduced in PANS/PANDAS | ** | Celik et al (2016)192 [CCS]; Stagi et al (2018)170 [CSS]; Frankovich et al (2015)2 [CCS]; Gromark et al (2019)7 [OS]; Gromark et al (2021)183 [OS]; Prato et al (2021)172 [SR]. |
| TSH, fT3 and fT4 | Blood | Increased in PANS/PANDAS, reduced in PANS/PANDAS | ** | Stagi et al (2014)169 [CCS]; Gagliano et al (2020)10 [OS]; Gromark et al (2019)7 [OS]; Gromark et al (2021)183 [OS]; Prato et al (2021)172 [SR]. |
Notes: The table shows an overview of PANS versus PANDAS and of PANS-associated putative biomarkers stratified on the basis of the totality of the evidence through a Likert scale from 1 to 3 (referring to the number of the supporting studies available – see the abbreviation explanation). The study design is also stated (see abbreviation). *Between 1 and 3 studies; **between 4 and 6 studies; ***= or > 7 studies.
Abbreviations: MA, meta-analysis; SR, systematic review; RCT, randomized controlled trial; OS, prospective or retrospective observational study; CCS, case-control study; CSS, cross-sectional study; CR and CS, case reports and case series; GL, guidelines.