Clinical Immunology

Symptoms and Warning Signs of APDS1

At a Glance

People with APDS1 often have recurrent respiratory infections, digestive problems, and baseline enlarged lymph nodes, but new or rapidly changing swelling, fever, breathing difficulty, confusion, or severe deterioration need prompt medical advice or emergency care.

Living with APDS1 means managing a body that is often in a state of high alert. Because your immune system is both underactive (prone to infection) and overactive (prone to swelling), it can be difficult to tell the difference between a routine symptom and a serious complication. This page outlines the common signs of APDS1 and, most importantly, the warning signs that require urgent medical attention ^[1]^[2].

Common Daily Symptoms

Most people with APDS1 experience a core set of symptoms that may fluctuate but are often present from a young age:

Sinopulmonary Infections: Recurrent ear infections, sinus infections, and pneumonia are very common, affecting over 90% of patients in some studies ^[1]^[3]. Over time, these can lead to bronchiectasis, where the lung’s airways become permanently scarred and widened ^[2].
Gastrointestinal Issues: Chronic diarrhea and abdominal pain (enteropathy) are frequent ^[4]. Some patients develop nodular mucosal lymphoid hyperplasia—small, benign bumps of immune tissue in the gut ^[1].
Chronic Swelling (Lymphoproliferation): It is common for the lymph nodes, tonsils, and spleen to be chronically enlarged ^[2]. For many, this swelling is “baseline” and does not necessarily mean there is an active infection or cancer ^[5].

Understanding Lymphadenopathy vs. Lymphoma

One of the most challenging aspects of APDS1 is that benign (non-cancerous) swelling and lymphoma (a type of blood cancer) both cause enlarged lymph nodes. While about 13% of patients may develop a malignancy, the vast majority of swelling in APDS1 is benign ^[6]^[7].

Crucially, you cannot reliably distinguish between a benign node, an infected node, and lymphoma just by touch or by observing response to antibiotics. A malignant node can be subtle, and an infected node can be firm or asymmetric. Antibiotics are not a diagnostic test for lymphoma. Any new, persistent, rapidly changing, hard/fixed, symptomatic, or otherwise concerning swelling must be discussed promptly with your treating team. Examination, imaging, laboratory evaluation, and sometimes a biopsy are needed ^[8]^[9].

Your Individualized Action Plan

Because APDS1 patients are immunodeficient, universal fever or symptom thresholds are unsafe. You must ask your team for a written, individualized sick-day plan detailing who to call during and after office hours. Do not self-start leftover antibiotics. Use the following categories to guide your response. When in doubt, always contact your immunology team.

1. Emergency Care (Go to the ER Immediately)

These signs may indicate sepsis (a life-threatening response to infection), septic shock, or a severe inflammatory crisis ^[9]^[10].

Difficulty Breathing: Rapid breathing, “sucking in” at the chest (retractions), or a bluish tint to the lips or nails ^[11].
Altered Mental Status: Sudden confusion, extreme sleepiness (hard to wake up), or fainting ^[12].
Poor Perfusion: Very cold hands and feet, or skin that looks mottled/purple ^[13].
Signs of HLH or Severe Crisis: Hemophagocytic Lymphohistiocytosis (HLH) is a rare but life-threatening medical emergency. Seek urgent assessment for persistent or recurrent fever with marked deterioration, rapid worsening of illness, new abdominal fullness or pain, new unusual bruising or bleeding, jaundice (yellowing skin/eyes), or severe new rash ^[14]^[15]^[16].

2. Same-Day Care (Call Your Doctor Now)

These signs suggest a serious infection or a transition in how the disease is acting that needs evaluation today.

Fever: Follow your written sick-day plan. Many patients—particularly those with neutropenia or on immune-modifying treatments—need same-day advice after a single fever ^[17].
Concerning Lymph Node Changes: Any node that grows rapidly or becomes painful ^[8]^[9].
Severe Viral Symptoms: Signs of severe EBV or CMV, such as intense throat pain that prevents swallowing or extreme lethargy ^[18]^[19].
New “B Symptoms”: Drenching night sweats, unexplained weight loss, or fevers that come and go ^[8].

3. Routine Monitoring (Discuss at Next Visit)

Stable Swelling: Nodes that are their usual baseline size.
Mild Fatigue: General tiredness that does not severely disrupt daily activities.

Common questions in this guide

What symptoms are common in APDS1?

APDS1 commonly causes repeated ear, sinus, and lung infections, including pneumonia. Chronic diarrhea, abdominal pain, and enlarged lymph nodes, tonsils, or spleen are also common, and repeated lung infections can lead to permanent airway damage called bronchiectasis.

When should someone with APDS1 go to the emergency room?

Seek emergency care for difficulty breathing, chest retractions, blue lips or nails, sudden confusion, extreme sleepiness, fainting, or cold and mottled skin. Fever with rapid worsening, severe weakness, new abdominal fullness or pain, unusual bleeding, yellowing of the skin or eyes, or a severe new rash also needs urgent assessment.

Does an enlarged lymph node in APDS1 mean lymphoma?

No. Chronic lymph node, tonsil, or spleen enlargement is often benign in APDS1, although people with APDS1 can develop lymphoma. You cannot reliably tell the difference by touch or by seeing whether antibiotics help, so new, persistent, rapidly growing, hard, fixed, or painful swelling should be assessed promptly.

What should I do if someone with APDS1 develops a fever?

Follow the written sick-day plan provided by the immunology team and contact the team when the plan says to do so. Fever thresholds are individualized, and people with neutropenia or those taking immune-modifying treatment may need same-day advice after one fever; do not start leftover antibiotics without medical guidance.

Which APDS1 symptoms need a same-day call to the doctor?

Call the treating team the same day for fever when directed by the sick-day plan, a rapidly growing or painful lymph node, severe throat pain that prevents swallowing, or extreme lethargy. Drenching night sweats, unexplained weight loss, or fevers that repeatedly come and go also need prompt discussion.

How should new or changing swelling be evaluated in APDS1?

A clinician may use an examination, imaging, and laboratory tests to evaluate a concerning lymph node or other swelling. Sometimes a biopsy is needed because infection, benign APDS1-related swelling, and lymphoma can look similar.

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Curated prompts to bring to your next appointment.

1.Does my/my child's current level of lymph node swelling match what you typically see in APDS1, or is it progresssing?
2.What exact symptoms should trigger a call to your office versus a trip to the ER?
3.How often will we monitor for chronic viruses like EBV and CMV, and at what viral load level do we start to worry?
4.Can you provide a written 'sick day plan' with clear instructions for fever, new cough, or breathing changes?
5.If we notice a new, firm, or rapidly growing node, what is the process for getting a 'second look' or a biopsy?

Key takeaways

APDS1 commonly causes recurrent ear, sinus, and lung infections, chronic diarrhea or abdominal pain, and enlarged lymph nodes, tonsils, or spleen.
Baseline lymph node swelling is often benign, but new, persistent, rapidly growing, hard, fixed, or painful nodes need prompt assessment because touch and antibiotic response cannot reliably rule out lymphoma.
People with APDS1 should follow an individualized written sick-day plan because fever thresholds vary, especially with neutropenia or immune-modifying treatment.
Difficulty breathing, blue lips, confusion, fainting, mottled or purple skin, or severe deterioration with fever requires emergency care.
Fever, painful or rapidly growing nodes, severe viral symptoms, drenching night sweats, unexplained weight loss, or recurrent fevers warrant same-day medical advice.

References (19)

1
Report of a Chinese Cohort with Activated Phosphoinositide 3-Kinase δ Syndrome.
Wang Y, Wang W, Liu L, et al.
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PMID: 30499059
2
Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry.
Maccari ME, Abolhassani H, Aghamohammadi A, et al.
Frontiers in immunology 2018; (9()):543 doi:10.3389/fimmu.2018.00543.
PMID: 29599784
3
Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.
Maccari ME, Wolkewitz M, Schwab C, et al.
The Journal of allergy and clinical immunology 2023; (152(4)):984-996.e10 doi:10.1016/j.jaci.2023.06.015.
PMID: 37390899
4
Successful Sirolimus Treatment for Korean Patients with Activated Phosphoinositide 3-kinase δ Syndrome 1: the First Case Series in Korea.
Kang JM, Kim SK, Kim D, et al.
Yonsei medical journal 2020; (61(6)):542-546 doi:10.3349/ymj.2020.61.6.542.
PMID: 32469178
5
Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.
Coulter TI, Chandra A, Bacon CM, et al.
The Journal of allergy and clinical immunology 2017; (139(2)):597-606.e4 doi:10.1016/j.jaci.2016.06.021.
PMID: 27555459
6
Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review.
Jamee M, Moniri S, Zaki-Dizaji M, et al.
Clinical reviews in allergy & immunology 2020; (59(3)):323-333 doi:10.1007/s12016-019-08738-9.
PMID: 31111319
7
Report of the Italian Cohort with Activated Phosphoinositide 3-Kinase δ Syndrome in the Target Therapy Era.
Barzaghi F, Moratti M, Panza G, et al.
Journal of clinical immunology 2024; (45(1)):58.
PMID: 39714594
8
Evaluation of Lymphoproliferative Disease and Increased Risk of Lymphoma in Activated Phosphoinositide 3 Kinase Delta Syndrome: A Case Report With Discussion.
Pham MN, Cunningham-Rundles C
Frontiers in pediatrics 2018; (6()):402 doi:10.3389/fped.2018.00402.
PMID: 30619796
9
Epstein-Barr Virus-Positive B-Cell Lymphoproliferative Disorder Complicated by Septic Shock in Activated PI3Kδ Syndrome: A Pediatric Case Report and Literature Review.
Zhao X, Ming X, Shang Z, et al.
Case reports in hematology 2026; (2026()):3644513 doi:10.1155/crh/3644513.
PMID: 42591980
10
Genetic Etiologies and Outcomes in Malignancy and Mortality in Activated Phosphoinositide 3-Kinase Delta Syndrome: A Systematic Review.
Büsch K, Memmott HL, McLaughlin HM, et al.
Advances in therapy 2025; (42(2)):752-771 doi:10.1007/s12325-024-03066-7.
PMID: 39636570
11
Updates on pediatric sepsis.
Cruz AT, Lane RD, Balamuth F, et al.
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PMID: 33145549
12
The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).
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PMID: 26903338
13
Accuracy of a Modified qSOFA Score for Predicting Critical Care Admission in Febrile Children.
Romaine ST, Potter J, Khanijau A, et al.
Pediatrics 2020; (146(4)) doi:10.1542/peds.2020-0782.
PMID: 32978294
14
Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults.
Hines MR, von Bahr Greenwood T, Beutel G, et al.
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PMID: 34605776
15
Hemophagocytic Lymphohistiocytosis in the Emergency Department: Recognizing and Evaluating a Hidden Threat.
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The Journal of emergency medicine 2021; (60(6)):743-751 doi:10.1016/j.jemermed.2021.02.006.
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16
A Rare Case of Activated Phosphoinositide 3-Kinase Delta Syndrome (APDS) Presenting With Hemophagocytosis Complicated With Hodgkin Lymphoma.
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PMID: 31033788
17
Predictor of Early Administration of Antibiotics and a Volume Resuscitation for Young Infants with Septic Shock.
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18
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19
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This APDS1 symptoms page is for informational purposes only and does not constitute medical advice. Your immunology team should provide an individualized sick-day plan and advise you about urgent symptoms.

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