Research

Tafenoquine-Atovaquone Combination Achieves Radical Cure and Confers Sterile Immunity in Experimental Models of Human Babesiosis

Pratap Vydyam, Anasuya C Pal, Isaline Renard, Meenal Chand, Vandana Kumari, Joseph C Gennaro, Choukri Ben Mamoun, Tafenoquine-Atovaquone Combination Achieves Radical Cure and Confers Sterile Immunity in Experimental Models of Human Babesiosis, The Journal of Infectious Diseases, 2024;, jiad315, https://doi.org/10.1093/infdis/jiad315

  • The 8-aminoquinoline antimalarial drug tafenoquine inhibits the growth of different Babesia species in vitro, is highly effective against Babesia microti and Babesia duncani in mice and protects animals from lethal infection caused by atovaquone-sensitive and -resistant B. duncani strains.
  • A combination of tafenoquine and atovaquone achieves cure with no recrudescence in both models of human babesiosis.
  • The elimination of B. duncani infection in animals following drug treatment also confers immunity to subsequent challenge.
  • The data demonstrate superior efficacy of tafenoquine plus atovaquone combination over current therapies for the treatment of human babesiosis and highlight its potential in providing protective immunity against Babesia following parasite clearance.
Microbes and Mental Illness: Past, Present, and Future
Bransfield RC, Mao C, Greenberg R. Microbes and Mental Illness: Past, Present, and Future. Healthcare (Basel). 2023 Dec 29;12(1):83. doi: 10.3390/healthcare12010083. PMID: 38200989; PMCID: PMC10779437.

The review highlights five infectious diseases linked to mental illness: toxoplasmosis, COVID-19, Lyme borreliosis, and streptococcal infections/PANDAS/PANS. It emphasizes the significant role of indirect infection mechanisms, such as inflammation, neuroinflammation, autoimmunity, and neurophysiological changes, in the development and progression of some mental illnesses. The persistence of these processes can lead to chronic effects on brain structure and function. Recognizing the microbial impact on mental health is crucial, and understanding this association may lead to increased use of antimicrobial and immune-modulating agents in psychiatric treatment, preventing and reducing mental illness morbidity, disability, and mortality. Clinicians must consider infectious diseases in explaining mental health symptoms, especially in cases of treatment-resistant conditions.

Treatment approaches must be individualized and often involve a multidisciplinary strategy to include three fundamental areas: addressing infections or contributors, implementing immune interventions, and managing resulting symptoms. Intervention choices depend on understanding the disease process, the interplay of disease contributors, and the primary driver of disease perpetuation and progression. Consider antimicrobials in cases of inadequate psychotropic response and potential infection. Immune-modulating interventions may be necessary for immune-mediated symptoms from active or prior infections or non-infection immune provocation. Factors like immune suppression, excessive inflammation, autoimmunity, and adaptive immunity failure influence immune intervention choices. Non-infection environmental factors, including toxin exposure, should be considered and minimized. For relapses, revisit effective past treatments; treatment-resistant cases may require exploring unused options. Regular treatment revisions are essential, guided by symptom improvement or disease changes. Ongoing assessment is crucial, recognizing that the initial cause may differ from what perpetuates the condition, leading to necessary treatment approach adjustments.

 

 

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Syndrome: A 10-Year Retrospective Cohort Study in an Italian Centre of Pediatric Rheumatology

La Bella S, Attanasi M, Di Ludovico A, Scorrano G, Mainieri F, Ciarelli F, Lauriola F, Silvestrini L, Girlando V, Chiarelli F, et al. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Syndrome: A 10-Year Retrospective Cohort Study in an Italian Centre of Pediatric Rheumatology. Microorganisms. 2024; 12(1):8. https://doi.org/10.3390/microorganisms12010008

PANDAS syndrome, a rare condition in prepubertal children, presents with sudden tic disorders and/or OCD following a documented GAS infection. Current classification criteria lack specificity, resulting in misdiagnosis. In our study, 61 patients were screened by the Pediatric Rheumatology unit for suspected PANDAS, but only 19 met the criteria. Tic disorders, especially in the eyes and head/neck, were predominant, with common vocal tics and less documented OCD. Treatment with antibiotics often led to clinical improvement. Larger, controlled studies are essential to understanding PANDAS characteristics and therapeutic responses comprehensively.

The Intricate Dance of Infections and Autoimmunity: An Interesting Paradox

Rao, A.P., Patro, D. The Intricate Dance of Infections and Autoimmunity: An Interesting Paradox. Indian J Pediatr (2023). https://doi.org/10.1007/s12098-023-04928-8

Besides genetic susceptibility, infections due to viruses, bacteria and protozoa have been implicated in the development of autoimmune diseases (AD). AD can be triggered in a genetically susceptible individual by infections that disrupt immunological tolerance towards self-antigens. Pathogens can initiate autoimmunity by way of molecular mimicry, bystander activation, epitope spreading or persistent infection with polyclonal activation. This review covers two main topics: (i) the mechanisms by which an infectious agent can trigger or worsen autoimmunity; and (ii) the correlation between specific infectious agents and AD in humans with special emphasis on multisystem inflammatory syndrome in children (MIS-C).

Caregiver Burden, Stress, and Relationship Cohesion Among Self-Identified Caregivers of Children with PANS
Tona JT, Ash J, Brown E, Campagna C, Kostek K, Lawton E, Rieth A, Tomita M. Caregiver Burden, Stress, and Relationship Cohesion Among Self-Identified Caregivers of Children with Pediatric Acute-Onset Neuropsychiatric Syndrome. J Child Adolesc Psychopharmacol. 2023 Nov;33(9):378-386. doi: 10.1089/cap.2023.0030. PMID: 37966363; PMCID: PMC10771873.
  • Among the 216 respondents, 79.6% exceeded the CBI threshold, indicating a need for respite in adult care receiver populations. On the CSAQ, 72.9% expressed high distress, 80.5% reported feeling overwhelmed, and 58.1% reported crying spells, meeting cutoffs for support/respite used in adult care receiver populations.
  • The majority of caregivers (85.5%) reported not having the desired degree of cohesion with their child on the IOS. Parents of children with more severe PNSS symptoms performed significantly worse on all measures (CBI: H = 57.83; CSAQ: F = 29.26; IOS: H = 38.04; p < 0.001 for all).

Common Comment Themes

  1. Severe caregiver and/or family emotional distress and trauma.
  2. Caregivers wondering what happened to their child.
  3. Lack of awareness and support among health and education professionals.
  4. Relationship strain with family, friends, and significant others.
  5. Financial and/or legal struggles due to their child’s diagnosis.

“Conclusion: There is strong need for support and respite for children with PANS and their families. Long-term effects including posttraumatic stress symptoms among family members should be studied.”

An updated review of pediatric autoimmune neuropsychiatric disorders associated with Streptococcus/pediatric acute-onset neuropsychiatric syndrome, also known as idiopathic autoimmune encephalitis: What the allergist should know
Hardin H, Shao W, Bernstein JA. An updated review of pediatric autoimmune neuropsychiatric disorders associated with Streptococcus/pediatric acute-onset neuropsychiatric syndrome, also known as idiopathic autoimmune encephalitis: What the allergist should know. Ann Allergy Asthma Immunol. 2023 Nov;131(5):567-575. doi: 10.1016/j.anai.2023.08.022. Epub 2023 Aug 25. PMID: 37634580.

Conclusion: Owing to the complexity and variability in ways patients with IAE may present to the allergist/immunologist office, an interdisciplinary approach is imperative to provide patients with the best medical care. Still, more research is needed to further elucidate the mechanism(s) and optimal treatment algorithm for IAE to facilitate broader recognition and acceptance of this condition by the medical community.

Factors Associated with Symptom Persistence in PANS: Part II—Presenting Features, Medical Comorbidities, and IVIG Treatment History
Denise Calaprice-Whitty, Angela Tang, and Janice Tona.Factors Associated with Symptom Persistence in PANS: Part II—Presenting Features, Medical Comorbidities, and IVIG Treatment History.Journal of Child and Adolescent Psychopharmacology.Nov 2023.365-377.http://doi.org/10.1089/cap.2023.0023
  • Significant relationships were identified among the 646 subjects, linking greater symptom persistence to higher rates of medical comorbidities.
  • Specific comorbidities associated with greater symptom persistence included rashes, headaches, chronic sinusitis, frequent diarrhea, and immune deficiencies.
  • Developmental diagnoses and respondent-perceived developmental lags were more prevalent in subjects with greater symptom persistence.
  • Subjects with greater symptom persistence reported PANS exacerbations associated with infections in close contacts, vaccinations, environmental triggers, and exacerbations of comorbidities.
  • PANS recurrences were more likely to be triggered by Epstein Barr Virus, mycoplasma, and sinus infections in subjects with greater symptom persistence.
  • More persistent PANS was linked to significantly higher frequencies of certain symptoms, including sleep disturbance, urinary incontinence, muscle pain, brain fog, sensory defensiveness, irritability, and aggression-related symptoms.
  • The effectiveness of intravenous immunoglobulin in combating symptoms was found to be less in cases of more persistent PANS.
  • Subjects with greater symptom persistence experienced more difficulty attending school.

“Conclusions: Our results suggest high symptom persistence in PANS to be associated with more pervasive medical and neuropsychiatric symptoms. Differences in symptom persistence are associated with both intrinsic (e.g., immune competence) and extrinsic (e.g., infections, treatment) factors. Because extrinsic factors are potentially modifiable, it is critical that providers be aware of current guidelines on PANS evaluation and treatment.”

Factors Associated with Symptom Persistence in PANS: Part I—Access to Care
Calaprice-Whitty D, Tang A, Tona J. Factors Associated with Symptom Persistence in PANS: Part I-Access to Care. J Child Adolesc Psychopharmacol. 2023 Nov;33(9):356-364. doi: 10.1089/cap.2023.0022. Epub 2023 Oct 30. PMID: 37902790.
  • Greater symptom persistence correlated with longer intervals between symptom onset and treatment (F = 4.43, p = 0.002).
  • Subjects with the least symptom persistence (>75% symptom-free days) were diagnosed by the first practitioner seen in 34% of cases, compared to 13% in those with the most persistent symptoms (symptoms every day) (L-R χ2 = 36.55, p < 0.0001).
  • Lack of access to expertise did not impede diagnosis and treatment for 52% of subjects with the least persistent symptoms, contrasting with 22% in those with the most persistent symptoms (L-R χ2 = 22.47, p < 0.0001).
  • Affordability did not impact diagnosis and treatment for 76% of subjects with the least persistent symptoms, whereas it affected 42% of those with the most persistent symptoms (L-R χ2 = 27.83, p < 0.0001).
  • Subjects whose PANS symptoms resolved with antibiotic treatment had less symptom persistence than others (χ2 = 23.27, p = 0.0001).
  • More persistently symptomatic subjects were more likely to discontinue intravenous immunoglobulin (IVIG) treatment due to access-to-care reasons.

“Conclusions: Unimpeded access to care for PANS is associated with more symptom-free days over reporting periods averaging approximately 4 years. Difficulty reaching expert providers, missed opportunities for diagnoses, and financial limitations may worsen outcomes. Practitioners, particularly primary providers, should adhere to published diagnostic and treatment guidelines promptly upon presentation.”

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Myth or Reality? The State of the Art on a Controversial Disease
La Bella S, Scorrano G, Rinaldi M, Di Ludovico A, Mainieri F, Attanasi M, Spalice A, Chiarelli F, Breda L. Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Myth or Reality? The State of the Art on a Controversial Disease. Microorganisms. 2023 Oct 13;11(10):2549. doi: 10.3390/microorganisms11102549. PMID: 37894207; PMCID: PMC10609001.
Despite significant advances in the understanding of the pathogenesis and therapeutic management of affected children, PANDAS remains a subject of dispute among experts. The controversial issues discussed in this paper can primarily be attributed to the challenges associated with establishing a definitive and timely correlation between the occurrence or recurrence of OCD and tic disorder in children who experience multiple GAS infections. Furthermore, it is important to note that the existing research examining the effectiveness of treatment techniques suffers from limitations in terms of sample size and rigorous inclusion criteria, which consequently hinders the provision of robust recommendations. Additional research is required to enhance our comprehension of the real prevalence of the disease, the precise pathogenic pathways involved, and the appropriate evidence-based methodology for its treatment.
Intravenous immunoglobulin treatment improves multiple neuropsychiatric outcomes in patients with pediatric acute-onset neuropsychiatric syndrome
Eremija J, Patel S, Rice S, Daines M. Intravenous immunoglobulin treatment improves multiple neuropsychiatric outcomes in patients with pediatric acute-onset neuropsychiatric syndrome. Front Pediatr. 2023 Oct 16;11:1229150. doi: 10.3389/fped.2023.1229150. PMID: 37908968; PMCID: PMC10613689.
  • A 5-year retrospective study was undertaken in Children’s Postinfectious Autoimmune Encephalopathy Center at University of Arizona.
  • 12 children diagnosed with PANS and treated with immunomodulatory IVIG dose who completed neuropsychological testing before and after treatment
  • Participants received 1–7 IVIG courses.
  • Improvement occurred in 11/12 patients, in one or multiple domains/subdomains, independently of time between disease onset and IVIG initiation (0–7 years)
  • Improvement was primarily seen in memory (58%), sensory-motor (37%) and visual-motor integration (30%).
  • 5/12 had hypogammaglobulinemia requiring ongoing IVIG replacement. Emphasizes the presumed role of immune dysfunction in disease pathogenesis.
  • 1/12 had isolated low IgA. 1/12 discontinued IVIG therapy due to severe adverse effects
Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections Manifestations in a Teenager

Sivakanthan A, Gedeon J, Sadaf S, et al. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections manifestations in a teenager. Prim Care Companion CNS Disord. 2023;25(5):23cr03505. October 5, 2023. https://doi.org/10.4088/PCC.23cr03505

This is a case of an 18-year-old male patient with PANDAS resistant to most treatments recommended in the literature. The patient lives with his parents, was recently home schooled, and has a history of autoimmune encephalitis, OCD, and Tourette’s disorder. He was admitted to an inpatient psychiatric unit for daily physical aggression toward his parents.