Parasitic Infections and Long COVID OK.pptx

Long COVID or Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually three months from the onset of COVID-19, with symptoms that last for at least two months and cannot be explained by an alternative diagnosis

1. D. Ibrahim Aboulasaad Tanta Faculty of Medicine Parasitology Department "Parasitic Infections and Long COVID: Unraveling Post-Infection Syndromes"

2. Session Objectives Understand Long COVID Learn what Long COVID is and how it affects the body. Recognize the Role of Parasitic Infections in Long COVID Understand how parasitic infections may influence or complicate Long COVID symptoms, especially in endemic regions. Explain the Immune Interactions Explore how chronic parasitic exposure and post-COVID immune dysregulation may interact and impact disease progression. Identify Diagnostic Challenges Learn about the overlapping symptoms and lab findings that make it difficult to distinguish parasitic co-infections from post-COVID syndromes. Highlight the Importance of Integrated Care Emphasize the need for a multidisciplinary approach in managing Long COVID patients, especially when parasitic infections are suspected. Promote Research and Awareness Encourage further studies on the prevalence, immune mechanisms, and outcomes of parasitic co-infections in Long COVID patients.

3. Long COVID Syndrome

4. Long COVID: Overview Definition : Long COVID or Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually three months from the onset of COVID-19, with symptoms that last for at least two months and cannot be explained by an alternative diagnosis . (WHO October 2021)

5. Common Symptoms: Fatigue Brain fog (cognitive dysfunction) Shortness of breath Chest pain Joint and muscle pain Sleep disturbances Anxiety and depression Loss of smell or taste Palpitations Possible Causes (Under Investigation): Persistent viral fragments Immune system overactivity or dysregulation Organ damage from the initial infection Blood clotting abnormalities Dysautonomia (dysfunction of the autonomic nervous system) Long COVID: Overview

6. High-Risk Groups: Individuals more likely to develop Long COVID: Hospitalized patients Older adults Females People with pre-existing autoimmune or chronic diseases Unvaccinated individuals. Estimated Prevalence of Long COVID Population Estimated % Developing Long COVID Source Hospitalized patients *** 50% or more *** JAMA, The Lancet General population (unvaccinated) ~10–30% WHO, CDC, studies Vaccinated individuals *** ~5–15% UK Health Security Agency Children and adolescents *** ~2–8% *** Paediatric studies (CDC, NIH)

7. Even vaccinated individuals still develop Long COVID !!! "Spotlight On" Why hospitalized patients have the highest Long COVID Risk? Why children and adolescents have the lowest Long COVID Risk?

8. Why Hospitalized Patients Have the Highest Long COVID Risk?  Severe Initial Illness: Hospitalized patients typically experience moderate to severe COVID-19, which leads to a higher chance of long-term complications.  Extended Inflammatory Response: Cytokine storms and prolonged immune activation can result in tissue damage and lingering symptoms.  Aggressive Treatments : Use of intubation, steroids, antivirals can lead to secondary effects or complications that mimic or worsen Long COVID.  Pre-Existing Conditions : Co-morbidities (e.g., diabetes, heart disease, obesity) increase vulnerability to persistent symptoms post-infection. Why Children and Adolescents have the lowest Long COVID risk? 1️⃣ Milder Initial Infections: 2️⃣ Stronger Innate Immune Response: 3️⃣ Fewer Co-morbidities: While Long COVID can occur in children, especially after MIS-C ((Multisystem Inflammatory Syndrome in Children), or severe infection, it is less common due to their mild disease course, strong immunity, and lower inflammatory response. MIS-C stands or: It’s a rare, delayed immune reaction that occurs 2–6 weeks after COVID-19 infection, even if the child had no or mild symptoms initially.

9. Can Vaccinated People Without Symptoms Get Long COVID? Yes — even vaccinated individuals who never tested positive or had symptoms can still develop Long COVID . Here's why: Undetected Infection : Asymptomatic or mild cases may go unnoticed, but still trigger lingering effects. Immune Response: The virus can cause long-lasting immune or inflammatory reactions, even if the acute phase was silent. Viral Remnants: Fragments of the virus might stay in the body and keep the immune system activated. Autoimmunity: COVID may cause the immune system to attack the body, leading to chronic symptoms. Vaccines Help, But Not Fully Protective: They lower risk but don’t prevent all cases of Long COVID. Answer:

10. Hypothesized mechanisms of long COVID pathogenesis The exact mechanisms are still under investigation, but several hypotheses have emerged, including : If you’ve recovered from COVID-19 but still feel unwell or have symptoms, you may have long COVID.

11. Hypothesized Mechanisms of Long COVID Pathogenesis Mechanism Description 1. Persistent Viral Reservoirs Remnants of SARS-CoV-2 may remain in tissues (gut, brain, etc.), keeping the immune system activated. 2. Chronic Inflammation Ongoing immune activation may cause low-grade inflammation, damaging organs and causing fatigue or pain. 3. Autoimmunity The virus may trigger the immune system to attack the body’s own cells, similar to autoimmune diseases 4. Endothelial Dysfunction The virus may damage blood vessels, leading to blood clotting issues and impaired oxygen delivery. https://doi.org/10.3389/fmicb.2021.698169

12. Cont. Hypothesized Mechanisms of Long COVID Pathogenesis Mechanism Description 5. Autonomic Nervous System Dysfunction Some patients show symptoms of dysautonomia, e.g., POTS , (Postural Orthostatic Tachycardia Syndrome), affecting heart rate, blood pressure, and temperature regulation. 6. Reactivation of Latent Viruses Viruses like Epstein-Barr (EBV) may reactivate, compounding symptoms. 7. Mitochondrial Dysfunction Mitochondria may not produce enough energy, leading to fatigue and brain fog. 8. Microclots and Hypoxia Microclots might reduce blood flow in tiny vessels, depriving tissues of oxygen. 9. Gut Microbiome Disruption COVID-19 may alter gut flora, affecting immunity and inflammation regulation. https://doi.org/10.3389/fmicb.2021.698169

13. summary table of Long COVID Syndrome — also known as Post-Acute Sequelae of SARS-CoV-2 infection (PASC) https://doi.org/10.3389/fmicb.2021.698169 System Affected Common Symptoms Hypothesized Mechanisms Notes Neurological Post-Acute Sequelae of SARS-CoV-2 Neuro-PASC: Brain fog, memory issues, headache, dizziness, anosmia Neuroinflammation, microglial activation, persistent viral RNA, hypoxia May resemble chronic fatigue syndrome (ME/CFS) Respiratory Shortness of breath, chronic cough Lung fibrosis, residual inflammation, and endothelial damage Can occur even after mild COVID-19 Cardiovascular Chest pain, palpitations, POTS (tachycardia) Autonomic dysfunction, myocardial inflammation, and microthrombi Includes long-term risk of myocarditis Musculoskeletal Fatigue, joint/muscle pain, weakness Mitochondrial dysfunction, systemic inflammation Similar to fibromyalgia-like features Gastrointestinal Nausea, diarrhea, appetite loss, abdominal pain Angiotensin-Converting Enzyme 2 (ACE2) receptor dysregulation, and gut microbiome alterations Often overlaps with post-infectious IBS

14. Continue, summary table of Long COVID Syndrome https://doi.org/10.3389/fmicb.2021.698169 System Affected Common Symptoms Hypothesized Mechanisms Notes Psychological / Psychiatric Depression, anxiety, PTSD, insomnia Chronic stress response, cytokine imbalance, psychosocial factors Mental health impact significant across all ages Dermatological Hair loss (telogen effluvium), rashes, "COVID toes" Microvascular injury, immune dysregulation Hair typically regrows within 3–6 months Renal Reduced kidney function, proteinuria Direct viral damage, microthrombi, inflammation Often in those with prior severe infection Endocrine / Metabolic New-onset diabetes, thyroid dysfunction Pancreatic β-cell infection, autoimmune triggers Reports of worsening pre-existing metabolic conditions Hematologic / Vascular Microclots, DVT, lingering coagulopathy Endothelial dysfunction, platelet activation May contribute to multi-system symptoms Immune / Inflammatory Chronic fatigue, relapsing symptoms Persistent cytokine elevation, viral reservoir hypothesis, autoimmunity "Relapsing-remitting" course in many cases

15. Most Recent Discoveries in Long COVID Syndrome (2024–2025) https://www.medrxiv.org/content/10.1101/2025.04.16.25325949.full.pdf Discovery Details Source Broken Bridge Syndrome (Neuroinflammatory subtype) Disruption in cerebellar-peduncle connectivity leads to persistent cognitive dysfunction and balance issues. Ziaja et al., 2025. medRxiv. PDF Persistent immune & metabolic dysregulation Identified specific long-term cytokine and lipid metabolism changes in Long COVID patients. Lucena Lage et al., 2025. medRxiv . PDF Neuro-PASC Biomarkers Blood biomarkers identified with 90% accuracy to detect neuro Post-Acute Sequelae of COVID (neuro-PASC). Koralnik et al., 2025. Neurology. Abstract Viral Persistence in CSF SARS-CoV-2 RNA found in cerebrospinal fluid of some long COVID patients with neurological symptoms . Cardoso et al., 2025. PLoS ONE. PDF

16. Cont. Most Recent Discoveries in Long COVID Syndrome (2024–2025) https://www.medrxiv.org/content/10.1101/2025.04.16.25325949.full.pdf Discovery Details Source Variant Connective Tissue Subtype Joint hypermobility syndromes (JHS). Joints move more than normal — sometimes called being “double-jointed. This extra flexibility causes pain, fatigue, or injury Lubell et al., 2025. medRxiv . PDF Oxidative stress as a central mechanism Redox imbalance ( the oxidants outnumber antioxidants ) identified as a key driver in long COVID symptoms such as fatigue and brain fog. Valente Coronel et al., 2025. Redox Report. PDF Microbiome Dysbiosis Gut microbiome disruption correlates with persistent inflammation and symptom relapse. Smail et al., 2025. Frontiers in Cellular and Infection Microbiology. Full Text Proteomic Signatures in Neurons SARS-CoV-2 may contribute to neurodegeneration via proteomic disruption in infected neurons. Li et al., 2025. bioRxiv . PDF

17. Post-Parasitic Syndromes

18. Many parasitic infections lead to chronic inflammation, persistent immune dysregulation, and metabolic dysfunction , even after the initial infection is cleared. Some parasitic diseases, such as Chagas disease and neurocysticercosis, have been linked to long-term neurological and cardiovascular complications, similar to those seen in Long COVID. In addition, parasites are known for their ability to evade and manipulate the host’s immune system , leading to prolonged immune suppression or hyperactivation , which can contribute to chronic symptoms long after the infection resolves. Definition : Post-parasitic syndromes refer to the chronic health conditions and persistent symptoms that occur after the apparent resolution of a parasitic infection. These syndromes can affect multiple organ systems and may last for months or years, even when the parasite is no longer detectable in the body Overview Post-Parasitic Syndromes

19. Characteristics of Post-Parasitic Syndromes: Feature Description Symptoms Can include fatigue, neurological deficits, gastrointestinal issues, cardiomyopathy, or immune dysfunction Pathophysiology Often linked to immune dysregulation, tissue scarring, autoimmunity, or residual inflammation Diagnosis Difficult to confirm; usually based on patient history, symptom persistence, and exclusion of reinfection. Analogy Similar to post-viral syndromes like Long COVID or post-Ebola syndrome.

20. Clinical Manifestations of Post-Parasitic Syndromes Chronic Fatigue and Myalgia: Similar to post-viral syndromes due to persistent immune activation. Cognitive Dysfunction ("Brain Fog") and Neuroinflammation: Seen in neurocysticercosis, chronic malaria, and Chagas disease . Autoimmune-like Disorders: Rheumatoid arthritis-like symptoms in leishmaniasis and schistosomiasis . Fibrosis and Organ Dysfunction: Chronic schistosomiasis and echinococcosis lead to hepatic and pulmonary fibrosis . Lymphatic filariasis leads to permeant lymphatic obstruction . Postural Orthostatic Tachycardia Syndrome (POTS): Observed in post-malaria syndromes , possibly due to autonomic dysfunction. Notes: Eosinophilia is a useful clue in many post-parasitic syndromes (especially helminths). Management often includes anti-parasitic agents + supportive or immunomodulatory therapy .

21. Parasitic Infection Post-Parasitic Syndrome Main Symptoms Mechanisms Malaria ( Plasmodium falciparum, vivax ) Post-Malaria Neurological Syndrome (PMNS) Cognitive dysfunction, seizures, anxiety, and POTS Neuroinflammation, cytokine dysregulation Trypanosoma cruzi (Chagas Disease) Chagasic Cardiomyopathy Heart failure, arrhythmia, stroke risk Autoimmunity, parasite persistence in cardiac tissue Toxoplasma gondii Neuropsychiatric disorders Depression, schizophrenia-like features, chronic fatigue Chronic CNS cysts, low-level neuroinflammation Schistosoma spp. Bladder fibrosis, liver cirrhosis, paraplegia Hematuria , abdominal pain, paralysis Granuloma formation, fibrosis Taenia solium (Neurocysticercosis) Epilepsy, cognitive decline Seizures, mental confusion, focal deficits Brain cyst degeneration triggering immune response Parasitic infections known to cause long-term effects after the infection has resolved. https://doi.org/10.1371/journal.pntd.0004539

22. Parasitic Infection Post-Parasitic Syndrome Main Symptoms Mechanisms Onchocerca volvulus Nodding syndrome, blindness Seizures, head nodding developmental delay, visual loss CNS involvement, immune-mediated neuronal damage Loa loa Loiasis-induced encephalopathy Coma, confusion, brain edema (rare) occurs after anti-filarial treatment, especially with ivermectin Wuchereria bancrofti (Filariasis) Elephantiasis, lymphedema Swollen limbs, disfigurement Lymphatic obstruction, chronic inflammation Trichinella spiralis Myalgia, fever, cardiac complications Muscle inflammation, heart issues Larval encystment in muscle Clonorchis sinensis / Opisthorchis spp. Cholangiocarcinoma (bile duct cancer) Jaundice, weight loss Chronic inflammation, mutagenic by-products Fasciola hepatica Biliary tract disease, cholangitis Right upper quadrant pain, fever Inflammation and fibrosis of bile ducts Cont. https://doi.org/10.1371/journal.pntd.0004539

23. Parasitic Infection Post-Parasitic Syndrome Main Symptoms Mechanisms Strongyloides stercoralis Hyperinfection syndrome GI issues, sepsis, lung failure Autoinfection cycle, immune failure Toxocara canis/ cati (Toxocariasis) Ocular & visceral larva migrans Visual loss, eosinophilia, asthma-like symptoms Larval migration, granuloma formation Echinococcus granulosus / multilocularis Hydatid Disease Cystic lesions in liver, lungs, brain Mechanical pressure, immune response Entamoeba histolytica Post- amebic colitis / liver abscess complications Chronic diarrhea, liver pain, weight loss Tissue invasion, immune-mediated scarring Giardia lamblia Post-infectious irritable bowel syndrome ( PI-IBS) Bloating, cramping, fatigue Altered microbiota, gut-brain axis dysfunction Cryptosporidium spp. Persistent diarrhea, malabsorption Chronic watery diarrhea Intestinal epithelial damage Cont. https://doi.org/10.1371/journal.pntd.0004539

24. The immunological tug-of-war between chronic parasitic exposure and post-viral immune dysregulation

25. Overview Concept The immune tug-of-war between chronic parasitic infections and post-viral immune dysregulation is clinically important because it can lead to unpredictable immune responses. While parasites often suppress or redirect the immune system to survive, post-viral conditions like Long COVID tend to trigger overactivation and inflammation. This opposing pull can mask symptoms, delay diagnosis, and complicate treatment. Inappropriate use of immunosuppressive therapies like steroids may worsen parasitic infections, especially in endemic regions. Chronic Parasitic Exposure Post-Viral (Long COVID) Immune Dysregulation Promotes immune tolerance or suppression Drives immune overactivation or autoimmunity Elevates regulatory T cells (Tregs) Increases inflammatory cytokines (IL-6, IFN-γ) Can reduce autoimmune risk (paradoxically) Can trigger or unmask autoimmune-like syndromes Skews toward Th2 immune response Often skews toward Th1/Th17 hyperactivation Immune System tug-of-war

26. What is the clinical relevance of this immune tug-of-war? Answer :

27. Long COVID vs Parasitic Infections: The Impacts on Immune System Long COVID and parasitic infections affect the immune system in opposite but overlapping ways. Long COVID is often linked to immune overactivation —causing chronic inflammation, autoimmunity, and cytokine imbalances. In contrast, many parasites suppress or manipulate the immune response to evade detection, leading to immune tolerance or ex h austion . When both conditions occur together , they can create an immune imbalance that confuses diagnosis, alters disease expression, and complicates treatment. Understanding these contrasting immune effects is crucial for proper clinical management, especially in regions where parasitic infections are common.

28. Autoimmune Syndromes: Long COVID vs Parasitic Infections: Emerging evidence suggests a complex interplay between Long COVID and parasitic infections in shaping autoimmune manifestations…… Although direct clinical studies are limited, the immunological tug-of-war between chronic parasitic exposure and post-viral immune dysregulation presents a compelling area for further investigation into protective or permissive roles in autoimmunity. COVID-19 and parasitic infections can sometimes share similar autoimmune consequences. This suggests that understanding the immune responses in these infections could shed light on the development and treatment of autoimmune diseases in general

29. System Long COVID Parasitic Infections Overlap / Notes Neurological ▶ Guillain-Barré Syndrome ▶ Autoimmune encephalitis ▶ Guillain-Barré Syndrome ▶ Neurocysticercosis Shared neuro-immune pathways Both conditions can trigger demyelinating or inflammatory responses Hematologic ▶ Autoimmune Hemolytic Anemia ▶ Immune Thrombocytopenia ▶ APS-like Syndrome (Antiphospholipid S.) ▶ Hemolytic anemia (e.g., malaria) ▶ Thrombocytopenia ▶ Transient antiphospholipid antibodies Parasitic infections can mimic APS Often transient and non-thrombotic Rheumatologic ▶ Rheumatoid arthritis–like ▶ Reactive arthritis ▶ SLE-like symptoms ▶ Rheumatoid arthritis–like ▶ Reactive arthritis ▶ SLE-like feature (e.g., Leishmania, Schistosoma) Clinical mimicry is common Important to distinguish from true autoimmune disease Autoimmune Manifestations: Long COVID vs Parasitic Infections Viruses. 2024 Aug 5;16(8):1256. doi : 10.3390/v16081256

30. System Long COVID Parasitic Infections Overlap / Notes Exocrine Glands ▶ Sjögren’s-like (dry eyes, mouth) ( متلازمة شوغرن ). ▶ Rare; possible mimicry Post-COVID patients may develop Sjögren’s-like symptoms Endocrine ▶ Autoimmune thyroiditis ( Hashimoto’s, Graves’ ) ▶ New-onset type 1 diabetes ▶ Possible protective effect from helminths Helminths may reduce autoimmunity risk Dermatologic ▶ Psoriasis ▶ Vitiligo ▶ Lichen planus ▶ Urticaria ▶ Immune-mediated eczema ▶ Vasculitis ⚠️ Skin affected in both by immune dysregulation Pulmonary ▶ MIS-A (Multisystem Inflammatory Syndrome – Adult) ▶ Eosinophilic pneumonia ▶ Pulmonary fibrosis ( Strongyloides ) Inflammatory lung complications are shared in both contexts Cont. Autoimmune Manifestations: Long COVID vs Parasitic Infections Viruses. 2024 Aug 5;16(8):1256. doi : 10.3390/v16081256

31. Autoimmune Syndromes Linked to Both COVID-19 and Parasitic Infections Viruses. 2024 Aug 5;16(8):1256. doi : 10.3390/v16081256 Autoimmune Syndrome Clinical Features Infectious Triggers Guillain-Barré Syndrome (GBS) Nerve inflammation, weakness/paralysis COVID-19, Toxoplasma , Plasmodium Systemic Lupus Erythematosus (SLE) Targets skin, joints, kidneys Infections via molecular mimicry Rheumatoid Arthritis (RA)-like Symptoms Chronic joint pain, stiffness Post-infectious immune activation Autoimmune Hemolytic Anemia (AIHA) Red blood cell destruction COVID-19, Babesia , Malaria Myocarditis / Pericarditis Heart tissue inflammation SARS-CoV-2, Trypanosoma cruzi Antiphospholipid Syndrome (APS)-like States Clotting disorder (antibodies attack phospholipids components of cell membrane) Long COVID, Schistosoma, Trypanosoma

32. What is a Cytokine Storm? A cytokine storm is an overproduction of immune signaling molecules called cytokines , which normally help coordinate the immune response. In this uncontrolled state, the immune system becomes hyperactive , releasing excessive amounts of cytokines into the blood too quickly.

33. Definition: A cytokine storm refers to the overproduction of inflammatory cytokines by the immune system. In the context of SARS-CoV-2 infection, this immune dysregulation is a major cause of severe illness and mortality, especially in critical patients. What Triggers the Cytokine Storm in COVID-19? When the coronavirus (SARS-CoV-2) enters the body, it infects lung cells. The immune system notices the virus and tries to fight it. Immune sensors in the body detect the virus's genetic material. This sets off warning signals (like turning on an alarm). The body starts making lots of immune chemicals (called cytokines) to attack the virus. In some people, this response goes out of control, causing a cytokine storm. This overreaction damages the lungs and other organs, which is why some COVID-19 patients get very sick. Cytokine Storm in COVID-19

34. Clinical Manifestations: ARDS (Acute Respiratory Distress Syndrome) Coagulopathy (blood clotting disorders) Multi-organ failure Increased ferritin, CRP, D-dimer, and IL-6 levels in lab tests Management Approaches: Corticosteroids: Dexamethasone has shown clear benefits. IL-6 inhibitors: Tocilizumab and sarilumab help mitigate storm severity. JAK inhibitors: Baricitinib as adjunct therapy in hospitalized patients. Supportive care: Oxygen, antivirals, and anticoagulants Cytokines Involved: IL-6 – Central mediator in COVID-19 cytokine storms. TNF- α, IL-1 β, IL-2, IL-10, IFN- γ – Associated with systemic inflammation . CXCL10, CCL2, and GM-CSF – Linked to lung infiltration and damage.

35. Cytokine Storm in Parasitic Infections Definition: Cytokine storms, or hypercytokinemia , refer to the excessive and uncontrolled release of pro-inflammatory cytokines that can lead to systemic inflammation, tissue damage, and sometimes multi-organ failure. Though they are more widely studied in viral infections (e.g., COVID-19), parasitic infections can also trigger this immune overreaction, especially in severe or disseminated disease. Mechanistic Insights: Pattern recognition receptors (PRRs) on immune cells detect parasitic molecules (e.g., glycosylphosphatidylinositols in malaria), activating NF- κ B and IRF pathways . Cytokines like TNF- α and IFN- γ , while essential for parasite control, can cause endothelial activation, vascular leakage, and immunopathology when overproduced. Immunoregulation via IL-10, TGF- β, and regulatory T cells often fails in cytokine storm scenarios.

36. Malaria ( Plasmodium spp.) Severe Plasmodium falciparum infections are classic examples. The parasite induces excessive release of TNF-α, IL-1β, IL-6, and IFN-γ. These cytokines contribute to cerebral malaria, fever, endothelial dysfunction, and hemolysis. Leishmaniasis (Leishmania spp .) Particularly in visceral leishmaniasis, the pro-inflammatory cytokine burst can suppress adaptive immunity and worsen tissue damage. Balance between IL-10 (anti-inflammatory) and IFN-γ determines disease progression. Trypanosomiasis ( Trypanosoma spp.) In African sleeping sickness (T. brucei), waves of parasitemia cause cyclical cytokine storms. These bursts are associated with neuroinflammation and the progression to the encephalitic stage. Toxoplasmosis ( Toxoplasma gondii ) In immunocompromised hosts (e.g., HIV+), cytokine storms can follow reactivation, driven by IL-12 and IFN-γ. Schistosomiasis ( Schistosoma spp.) Chronic infections can result in granuloma formation due to sustained cytokine signaling (IL-4, IL-13, TNF-α). Severe hepatic or pulmonary schistosomiasis involves elements of a localized cytokine storm.

37. Mast Cell Activation Syndrome Mast Cell Activation Syndrome (MCAS) is a chronic condition characterized by the inappropriate activation and release of chemical mediators from mast cells, a type of immune cell involved in allergic responses and inflammation.

38. MCAS and COVID-19: Mast Cell Activation Syndrome (MCAS) is a condition where mast cells (a type of immune cell) release too many inflammatory chemicals like histamine and cytokines. These cells are usually involved in allergic reactions, but in MCAS, they become overly sensitive and reactive. Aspect MCAS COVID-19 (severe/long) Immune trigger Non-specific, chronic Viral (SARS-CoV-2) Key immune cells Mast cells T cells, macrophages, mast cells Chemicals released Histamine, tryptase, IL-6 IL-6, TNF- α, IL-1 β Overlap symptoms Fatigue, brain fog, GI issues Fatigue, brain fog, dyspnea Possible interventions Antihistamines, cromolyn sodium Anti-inflammatories, IL-6 blockers, antihistamines SARS-CoV-2 may stimulate mast cells in the lungs and other tissues. This leads to the release of histamine, cytokines (like IL-6), and leukotrienes, contributing to inflammation and symptoms like fatigue, rashes, and breathing difficulty. Summary Table

39. MCAS and Parasitic infections In MCAS (Mast Cell Activation Syndrome), mast cells release too many chemicals—even when not needed—causing symptoms like itching, stomach issues, and fatigue. Mast cells play a key role in fighting parasites. Parasitic infections can strongly activate mast cells, which is a normal immune response. In people with MCAS, parasitic infections can worsen symptoms or trigger flare-ups due to extra mast cell activation . Common MCAS-like symptoms during parasitic infections: Skin rashes or hives Diarrhea or cramps Flushing or rapid heartbeat Treatment may involve: Anti-parasitic medication to remove the parasite Antihistamines or mast cell stabilizers to control MCAS symptoms Proper diagnosis is important: MCAS can mimic parasite-related symptoms and vice versa.

40. L ink between MCAS (Mast Cell Activation Syndrome) and parasitic infections: ARR Summary Table (Accurate, Relevant, and Readable) formats Aspect Key Fact Easy Explanation Immune Role of Mast Cells Mast cells defend against parasites by releasing inflammatory substances. Mast cells help fight parasites by releasing chemicals. What is MCAS? MCAS causes mast cells to release chemicals excessively, even without infection. MCAS means your immune cells overreact and cause problems. Effect of Parasitic Infections Parasites activate mast cells as a natural immune defense . Parasites wake up mast cells to help defend your body. MCAS Triggering by Parasites Parasitic infections can trigger or worsen MCAS flares. Parasites might make MCAS worse in some people.

41. Cont. ARR Summary Table Aspect Key Fact Easy Explanation Common Symptoms Symptoms include rashes, diarrhea, flushing, and fatigue. You might get skin, stomach, or blood pressure issues. Long-Term Impact Persistent parasitic infections may contribute to ongoing mast cell activation. Ongoing infections can keep your mast cells too active. Treatment Approach Anti-parasitic drugs and mast cell stabilizers are used together. Doctors treat both the parasite and the overactive cells. Diagnosis Tip Differentiating between MCAS and parasite symptoms is essential for proper care. Doctors need to check if it's MCAS or a parasite—or both! https://doi.org/10.1038/nri1460 & https://doi.org/10.1038/nri2018

42. The bidirectional relationship between Long COVID and parasitic infections: The interplay between Long COVID and parasitic infections presents significant challenges in diagnosis and management. Clinicians should maintain a high index of suspicion for co-infections and consider comprehensive screening, especially in endemic areas or in patients with persistent or unexplained symptoms.​

43. Impact of Parasitic Infections on Long COVID Parasite Epidemiol Control. 2023 Mar 30;21:e00299. doi : 10.1016/j.parepi.2023.e00299 Effect How It Happens Immune Confusion Parasites can suppress or skew the immune response, potentially masking Long COVID inflammation . Overlapping Symptoms Fatigue, GI upset, and brain fog from parasites may mimic or worsen Long COVID symptoms . Treatment Complications If steroids are given for Long COVID without checking for parasites, they can cause severe infections like Strongyloides. Diagnostic Delay Parasites may cause false assumptions about Long COVID progression , delaying accurate care. Parasitic infections may influence the development, severity, or persistence of Long COVID by affecting the immune system. In areas where parasites are common A

44. Impact of Long COVID on Parasitic Infections. Parasite Epidemiol Control. 2023 Mar 30;21:e00299. doi : 10.1016/j.parepi.2023.e00299 Effect How It Happens Weakened Immunity Long COVID may cause T-cell exhaustion or cytokine imbalances , making it easier for parasites to reactivate or spread . Microbiota Disruption COVID-19 often affects gut flora, increasing the risk of intestinal parasites like Giardia. Delayed Detection Long COVID symptoms (e.g., fatigue, pain) may hide signs of parasitic infection . Higher Risk in Endemic Areas In areas where parasites are common, Long COVID may increase disease burden and complications . Long COVID may affect the course, detection, or reactivation of parasitic infections, particularly in individuals with underlying or latent parasitic diseases. B

45. How COVID-19 May Alter Host Immunity and Predispose to Parasitic Infections? Immune Suppression: Reduced T-cell activity and immune exhaustion lower the body’s defense against parasites. Th2 Immune Shift: COVID-19 may skew immunity, weakening the response to intracellular parasites. Steroid Use: Treatments like corticosteroids can reactivate latent parasites (e.g., Strongyloides, Toxoplasma). Gut Barrier Damage: Disruption of the gut microbiome and mucosal barriers may aid parasite entry and survival. Healthcare Disruption: In low-resource areas, pandemic strain may delay diagnosis and treatment of parasitic diseases. COVID-19, caused by SARS-CoV-2, can lead to significant immune dysregulation, which may increase a person's vulnerability to parasitic infections — especially in endemic areas. Here's how: Together, these effects create a higher risk of new, reactivated, or worsened parasitic infections in people recovering from COVID-19.

46. Reported Cases of Parasitic Reactivation or Coinfections in Long COVID Patients These cases underscore the importance of considering parasitic co-infections in patients with Long COVID, especially in endemic regions or among individuals with risk factors for parasitic infections. Clinicians should maintain a high index of suspicion and consider appropriate screening and management strategies.

47. Reported Cases of Parasitic Coinfections 1 . Strongyloides stercoralis Hyperinfection Syndrome (SHS) Case Report: A 63-year-old man from Cambodia developed disseminated strongyloidiasis after receiving high-dose corticosteroids and tocilizumab for COVID-19 treatment. The immunosuppressive therapy likely triggered the hyperinfection. ​ 2. Schistosomiasis and Pulmonary Vascular Disease (PVD) Hypothetical Link: A review suggests that chronic schistosomiasis may exacerbate COVID-19-induced pulmonary vascular remodeling, potentially leading to PVD. The overlapping pathophysiological mechanisms warrant further investigation. ​ 3. Lophomonas blattarum Co-infection Lophomonas blattarum is a protozoan parasite found in the respiratory tract. It is believed to originate from cockroach intestines, and human infection likely occurs through inhalation of aerosolized cysts. Case Report : A 33-year-old pregnant woman was diagnosed with concurrent COVID-19 and Lophomonas blattarum infection. The patient presented with respiratory symptoms, and the co-infection was confirmed using molecular techniques. 4. Malaria and COVID-19 Co-infection Systematic Review identified malaria as the most frequently reported parasitic co-infection with COVID-19. The overlapping symptoms can complicate diagnosis and management. ​

48. Reported Cases of Parasitic Coinfections 5. Visceral Leishmaniasis Co-infection Case Report: A patient from the Middle East was diagnosed with both COVID-19 and visceral leishmaniasis. The co-infection posed diagnostic challenges due to overlapping clinical features. ​ 6. Toxoplasma gondii It was shown that almost half of COVID-19 patients had previous exposure to T. gondii through the presence of IgG, and a small percentage, 2%, showed active infection through IgM detection. Reactivation of latent Toxoplasma infection noted in some COVID-19 cases. Risk increased with immune dysfunction or corticosteroid therapy. 7. Entamoeba histolytica Reactivation or symptomatic flare-ups in COVID-affected individuals. GI tract disruption may play a role. 8. Giardiasis Post-COVID patients may present with persistent or re-emergent symptoms. Gut microbiome disruption may increase susceptibility. 9. Intestinal Parasitic Infections in COVID-19 Patients This case-control study conducted in Iran found a higher prevalence of intestinal parasitic infections (13%) in COVID-19 patients compared to healthy controls (7.5%). The most common parasites identified were Blastocystis sp., Giardia lamblia, and Entamoeba coli. The study highlights the importance of considering parasitic infections in the differential diagnosis of gastrointestinal symptoms in COVID-19 patients BMC Public Health volume 24, Article number: 2885 (2024)

49. HDM Allergy in Long COVID Coinfection People with House Dust Mite (HDM) allergies may face worse or prolonged symptoms if infected with COVID-19, especially in Long COVID cases. The allergy causes airway inflammation and immune suppression, which weakens the body’s ability to fight off viruses like SARS-CoV-2. This overlap can lead to: More severe respiratory symptoms Delayed recovery from COVID-19 Higher risk of persistent inflammation (Long COVID) Allergic individuals show changes in ACE2 receptor (Angiotensin-Converting Enzyme 2) expression (used by the virus to enter cells) and reduced antiviral immune responses. Monitoring eosinophils and IgE levels can help track Long COVID risk. Interestingly, some HDM-related molecules might offer protective, anti-inflammatory effects—but more research is needed.

50. https://www.nature.com/articles/s41467-023-37470-4 Sey & Warris (2024). The gut-lung axis and pulmonary infections... Oxford Open Immunology Mechanism HDM Allergy Impact on Long COVID Inflammation Heightens airway and systemic inflammation Immune suppression Reduces antiviral responses, prolongs viral effects ACE2 modulation Increases SARS-CoV-2 entry risk Gut-lung axis Aggravates immune dysregulation Biomarkers Eosinophils & IgE can help monitor symptom persistence Therapeutic Potential Some HDM-related molecules might have protective roles Summary of HDM Effects: Table format

51. Diagnostic challenges: Post-COVID vs. Parasitic Infections . Post-COVID and parasitic infections often present with overlapping symptoms making diagnosis particularly challenging. In endemic areas or among immunosuppressed individuals, parasitic infections may be misinterpreted as prolonged COVID symptoms or vice versa. This overlap can lead to delayed or incorrect diagnoses, especially when standard post-COVID care pathways do not include parasitic screening. Additionally, the immune dysregulation seen in Long COVID may mask or alter typical parasite-related lab findings, complicating interpretation.

52. Diagnostic challenges: Post-COVID vs. Parasitic Infections . 1. Overlapping Symptoms : Both can cause: Fatigue GI symptoms (diarrhea, bloating) Neurological issues (brain fog, headache) Muscle/joint pain 2. Immune System Confusion Post-COVID immune dysregulation may mask or mimic parasitic diseases. Parasitic infections may reactivate under weakened immunity. 3. Nonspecific Lab Results Common findings like elevated eosinophils, inflammatory markers, or antibodies may appear in both. 4. Steroid Use Complications Immunosuppressive treatment in Long COVID can worsen undiagnosed parasitic infections, e.g., Strongyloides . 5. Delayed or Misdiagnosed Cases In endemic regions, parasites may be overlooked if focus remains on post-viral syndrome. Requires broad differential diagnosis and careful clinical history.

53. Diagnostic challenges: Post-COVID vs. Parasitic Infections . Overlapped criteria

54. Integrated Diagnostic Approach for Co-Infection Clinical history  Symptom evaluation  Laboratory Testing  Imaging & consultation  Balanced treatment  Ongoing monitoring Integrated Approach to COVID-19 + Parasitic Co-Infection

55. Clinical History Travel or residence in endemic areas Recent or prior COVID-19 infection Use of steroids or immunosuppressants 2. Symptom Overlap Evaluation Distinguish shared symptoms: Fatigue, GI upset, fever, rash Neurological or respiratory issues Look for parasite-specific signs 3. Laboratory Testing CBC with differential (look for eosinophils) Inflammatory markers (CRP, ESR) COVID-19 PCR or antibody testing Stool O&P (ova & parasites), antigen or PCR tests Serology for suspected. 4. Imaging & Specialist Input Chest imaging for COVID-19 pneumonia Brain/spinal imaging if neurological signs present Infectious disease or tropical medicine consult for complex cases 5. Balanced Treatment: COVID Management: Antivirals (e.g., nirmatrelvir), steroids (if indicated), supportive care Parasitic Treatment: Specific antiparasitic: Pre-treatment in high-risk patients before immunosuppression 6. Ongoing monitoring Track response to both treatments. Watch for relapse or complications. Repeat labs/imaging as needed. Integrated Approach to COVID-19 + Parasitic Co-Infection

56. Summary Sheet: Guideline for Long COVID and Parasitic Coinfection 1️⃣ Clinical Assessment: - Check COVID history, symptoms ≥4 weeks, endemic exposure, steroid use 2️⃣ Investigations: - CBC w/ eosinophils, CRP, Stool O&P x3, parasite PCR/serology, COVID PCR/Ab 3️⃣ Risk Stratification: - Immunosuppressed, elderly, steroid use, severe/multiple symptoms 4️⃣ Treatment: - Long COVID: supportive; avoid steroids if parasite risk - Parasites: Ivermectin, Metronidazole, Albendazole as appropriate 5️⃣ Monitoring & Follow-Up: - Track symptoms, retest if needed, manage side effects - Refer to ID/Gastro if unclear - 1–3-month follow-up & education https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1

57. Conclusion Post-COVID Syndrome is a complex condition that often presents with symptoms overlapping those of parasitic infections—such as fatigue, gastrointestinal disturbances, and neurological complaints. These similarities can obscure co-infections, particularly in individuals living in endemic regions or those who are immunosuppressed. Shared immuno-inflammatory pathways between SARS-CoV-2 and parasitic pathogens—like immune dysregulation, cytokine imbalance, and autoimmunity—further complicate diagnosis. To effectively address parasitic co-infections in the context of Long COVID, it is recommended to include parasitic coinfection assessments in Long COVID clinics and post-viral care guidelines, especially in global health settings. A multidisciplinary approach should be encouraged, fostering collaboration among infectious disease specialists, tropical medicine practitioners, immunologists, and post-COVID care teams. Additionally, further research is needed to understand the prevalence, immune mechanisms, and clinical outcomes associated with parasitic co-infections in individuals experiencing Long COVID. Delayed recognition of parasitic infections can lead to prolonged illness, delayed recovery, and avoidable complications. To mitigate these risks, a vigilant, integrated diagnostic strategy is essential. Clinicians should maintain a high index of suspicion and incorporate travel history, symptom overlap, and appropriate laboratory screening to differentiate and manage these often-overlooked co-infections effectively.