Frequent Infections: Labs, Root Causes, and Next Steps

Why Do I Keep Getting Infections?

Adults who get four or more significant infections per year, or who notice that each illness runs longer and harder than it should, have an immune system that is not clearing pathogens at normal speed. The reason can be primary (the immune system itself is defective) or secondary (something else, a hormone imbalance, a chronic disease, a drug, or a nutritional gap, is suppressing an otherwise intact immune system).

Primary vs. Secondary Immunodeficiency

Primary immunodeficiencies (PIDs) are genetic conditions present from birth, though many are not diagnosed until adulthood. Common variable immunodeficiency (CVID) is the most frequently diagnosed PID in adults. The European Society for Immunodeficiencies registry, which now contains data on more than 25,000 patients, shows that the median delay from first symptoms to CVID diagnosis is 4.1 years, meaning most patients have been mismanaged for years before the correct label is applied. (1)

Secondary immunodeficiencies are far more common and include:

• Uncontrolled type 2 diabetes (hyperglycemia impairs neutrophil chemotaxis and phagocytic killing)
• Hypothyroidism (thyroid hormone directly regulates natural killer cell activity)
• Low testosterone in men (hypogonadism reduces CD4+ T-cell counts)
• Chronic corticosteroid use
• Protein-calorie malnutrition or severe vitamin D deficiency
• HIV infection (still undiagnosed in an estimated 13% of infected Americans per the CDC)

The Infection Pattern Matters

The type of organism causing your infections points strongly toward the immune compartment that is failing:

• Repeated bacterial sinopulmonary infections (pneumonia, sinusitis, otitis) suggest antibody deficiency, most often low IgG or IgA.
• Fungal infections (oral thrush, recurrent vaginal candidiasis, Pneumocystis) suggest T-cell or innate immune dysfunction.
• Recurrent infections with encapsulated bacteria such as Streptococcus pneumoniae or Haemophilus influenzae point toward splenic dysfunction or complement deficiency.
• Opportunistic infections in an otherwise healthy adult should trigger HIV testing immediately.

Keeping a written log of every infection, the organism identified (if cultured), the antibiotic used, and the time to resolution gives your physician the pattern recognition data needed to order the right tests on the first try.

Which Labs Should Be Ordered First?

The initial workup for recurrent infections is organized into three tiers. Your primary care physician can order Tier 1 on the same day as your visit. Tier 2 requires more specialized testing. Tier 3 is typically ordered or interpreted by an immunologist.

Tier 1: Broad Screening (Order on Day One)

Complete Blood Count with Differential (CBC-diff). A CBC-diff quantifies all white cell populations. Neutrophil counts below 1,500 cells per microliter (absolute neutropenia) impair bacterial killing. Lymphocyte counts below 1,000 cells per microliter suggest T-cell depletion. The CBC-diff costs roughly $10 to $30 and is available at every commercial lab.

Comprehensive Metabolic Panel (CMP). Glucose, kidney function, and liver enzymes flag diabetes, renal tubular acidosis, and hepatic disease, all of which suppress immunity through distinct pathways.

Thyroid Stimulating Hormone (TSH). Hypothyroidism is present in roughly 5% of the US adult population per the American Thyroid Association, and it is reversible. A TSH above 4.0 mIU/L warrants free T4 measurement and possible treatment.

HbA1c. An HbA1c at or above 6.5% confirms diabetes. At or above 8%, diabetic immune impairment is clinically significant.

25-hydroxyvitamin D. The Endocrine Society defines vitamin D deficiency as a level below 20 ng/mL. A 2021 meta-analysis in the BMJ (18 randomized trials, N=75,541) confirmed that vitamin D supplementation reduced the risk of acute respiratory infections, with the largest benefit in people who started the trial severely deficient. (2)

HIV antigen/antibody combination test (Ag/Ab). The CDC recommends HIV screening for all adults aged 15 to 65 at least once, and annually for people with ongoing risk. (3)

Total protein and albumin. Serum albumin below 3.5 g/dL indicates protein malnutrition, which collapses both cell-mediated and humoral immunity.

Tier 2: Targeted Immune Markers

If Tier 1 is unrevealing and infections continue, your physician should add:

Serum immunoglobulins (IgG, IgA, IgM, IgE). Low IgG (below 700 mg/dL in most lab reference ranges) is the hallmark of antibody deficiency syndromes, including CVID and selective IgA deficiency. Selective IgA deficiency, defined as serum IgA below 7 mg/dL with normal other immunoglobulins, affects 1 in 300 to 700 people and is the most common primary immunodeficiency overall. (4)

Vaccine antibody titers. After confirming low IgG or IgA, the next step is to test whether the patient can mount an antibody response. Physicians typically check pre- and post-pneumococcal vaccine titers at four to eight weeks. Failure to achieve a fourfold rise in titers to at least 70% of serotypes tested is diagnostic criteria for CVID per the ESID/PAGID consensus guidelines. (5)

Complement C3 and C4. Complement deficiency predisposes specifically to Neisseria infections (meningococcal meningitis, disseminated gonococcal disease) and severe pneumococcal disease. Low C4 with normal C3 often points to hereditary angioedema rather than susceptibility to infection.

Ferritin and iron studies. Iron deficiency impairs lymphocyte proliferation and myeloperoxidase-dependent bacterial killing. A ferritin below 30 ng/mL is considered deficient even when hemoglobin is still normal.

Zinc level (serum zinc, fasted). Zinc is required for thymulin activity and T-cell maturation. Deficiency is common in older adults and in people on proton pump inhibitors, which reduce zinc absorption by roughly 40%.

Tier 3: Specialist-Level Immune Phenotyping

Lymphocyte subset panel (CD3, CD4, CD8, CD19, CD16/56). This panel, ordered or interpreted by an immunologist, identifies specific T-cell, B-cell, and NK-cell deficiencies. A CD4 count below 200 cells per microliter in an HIV-negative adult is a red flag for a severe combined immunodeficiency variant or severe drug-induced lymphopenia.

Neutrophil oxidative burst (dihydrorhodamine flow cytometry). This test screens for chronic granulomatous disease (CGD), a rare condition in which neutrophils engulf but cannot kill catalase-positive bacteria and fungi.

CH50 (total hemolytic complement). A functional assay that detects terminal complement pathway defects not caught by C3/C4 alone.

Hormone Imbalances That Quietly Suppress Immunity

This is an area where telehealth medicine and conventional primary care diverge most sharply. Standard infectious disease workups rarely include hormone panels. Evidence shows they should.

Testosterone and Male Immune Function

Testosterone acts on androgen receptors expressed on T cells, B cells, and macrophages. Hypogonadism (total testosterone below 300 ng/dL per the American Urological Association guideline) is associated with reduced CD4+ helper T-cell activity and elevated pro-inflammatory cytokines. (6) Men with frequent respiratory or skin infections and low libido, fatigue, or poor sleep should have a morning total and free testosterone drawn before 10 a.m.

Testosterone replacement therapy (TRT), when prescribed for confirmed hypogonadism, normalizes several immune parameters. One 52-week randomized controlled trial in hypogonadal men showed that TRT increased CD4+ T-cell counts by a statistically significant margin compared to placebo (P<0.01). (7)

Thyroid Hormone and Innate Immunity

Thyroid hormone receptors are expressed on natural killer cells and macrophages. Hypothyroidism reduces NK cell cytotoxicity, slows macrophage phagocytosis, and impairs mucociliary clearance, the first physical barrier against respiratory pathogens. A 2020 study in Frontiers in Endocrinology found that patients with Hashimoto's thyroiditis had significantly lower NK cell activity than euthyroid controls, and that six months of levothyroxine treatment partially restored NK function. (8)

Cortisol: Too Much Is As Bad As Too Little

Chronic psychological stress elevates cortisol, which suppresses Th1 immune responses and reduces secretory IgA at mucosal surfaces. Patients on long-term oral prednisone doses above 10 mg per day for more than 30 days meet the threshold for clinically significant immunosuppression and should be considered for prophylactic antibiotics per IDSA guidelines. (9) Paradoxically, adrenal insufficiency (low cortisol) also impairs immune regulation, causing uncontrolled inflammation that paradoxically leaves patients vulnerable to secondary bacterial infections.

Nutritional Deficiencies as Correctable Causes

Nutritional gaps are the most treatable causes of secondary immunodeficiency, and they are frequently missed in standard workups.

Vitamin D

The 2021 BMJ meta-analysis cited above showed a 12% reduction in acute respiratory infection risk with supplementation across all participants, rising to 70% reduction in people starting with 25-OHD below 10 ng/mL. The Endocrine Society recommends 1,500 to 2,000 IU of vitamin D3 daily for adults at risk of deficiency, with a target serum level of 40 to 60 ng/mL for optimal immune function. (10)

Zinc

A Cochrane review of 28 trials found that zinc acetate or zinc gluconate lozenges started within 24 hours of cold symptom onset reduced duration by 33%. (11) For adults with documented zinc deficiency, elemental zinc 25 to 45 mg daily for eight to twelve weeks is the standard repletion protocol.

Iron

Iron-deficiency anemia blunts T-lymphocyte proliferative response by up to 30% in controlled studies. Oral ferrous sulfate 325 mg (65 mg elemental iron) taken three times daily with vitamin C remains the standard repletion regimen. Recheck ferritin at eight weeks to confirm response before switching to IV iron.

When to Refer to an Immunologist or Infectious Disease Specialist

Not every patient with recurrent infections needs a subspecialist. The following clinical decision framework, developed by the HealthRX medical team to standardize referral thresholds, identifies who should go and who can be managed in primary care or telehealth:

Refer to Clinical Immunology if:

• IgG is below 500 mg/dL on two separate measurements at least four weeks apart
• Vaccine antibody titers show impaired response after pneumococcal rechallenge
• CD4 count is below 300 cells per microliter in an HIV-negative patient
• Neutrophil oxidative burst is abnormal
• Family history of PID or unexplained early death from infections exists
• Patient has had any Pneumocystis jirovecii pneumonia, disseminated mycobacterial infection, or invasive aspergillosis

Refer to Infectious Disease if:

• A single organism (e.g., Staphylococcus aureus, Pseudomonas) is causing repeated infections at different body sites
• Infections fail to respond to two or more courses of appropriate antibiotics
• Blood cultures have grown the same organism on two separate occasions
• Patient has traveled to or immigrated from a TB-endemic region and has constitutional symptoms

Manage in Telehealth or Primary Care if:

• Infections are confined to upper respiratory tract with no hospitalizations
• CBC-diff, immunoglobulins, and complement are all within normal limits
• An identifiable cause (vitamin D deficiency, hypothyroidism, poorly controlled diabetes) is found and treatment has been started
• Patient is responding to initial management within eight to twelve weeks

Treatment Options by Cause

Antibody Deficiency: Immunoglobulin Replacement Therapy

Confirmed antibody deficiency (CVID, XLA, or secondary hypogammaglobulinemia) is treated with immunoglobulin replacement, either intravenous (IVIG) or subcutaneous (SCIG). The standard IVIG dose is 400 to 600 mg/kg every three to four weeks, titrated to maintain trough IgG above 700 to 800 mg/dL. The 2019 American Academy of Allergy, Asthma, and Immunology practice parameters state that "the primary goal of IgG replacement therapy is to reduce the frequency and severity of bacterial infections." (12) SCIG (brand names Hizentra and Cuvitru) allows self-administration at home weekly, which significantly improves adherence for many patients.

Hormone Replacement: TRT and Thyroid

For men with confirmed hypogonadism and recurrent infections, TRT via weekly testosterone cypionate 100 to 200 mg IM, or daily topical testosterone 1.62% gel, is the standard-of-care starting regimen. Thyroid optimization with levothyroxine targeting a TSH of 1.0 to 2.5 mIU/L is recommended by most endocrinologists for patients with symptomatic hypothyroidism and immune complaints.

Antimicrobial Prophylaxis

Patients with documented antibody deficiency who are unable to access IVIG, or who continue to have breakthrough infections on replacement therapy, may be offered prophylactic antibiotics. Azithromycin 250 mg three times weekly reduced pulmonary exacerbations by 27% in a randomized trial of CVID patients with bronchiectasis (N=83). (13)

Stem Cell Transplantation

Severe combined immunodeficiency (SCID) and some other primary immunodeficiencies are curable with hematopoietic stem cell transplantation (HSCT). Survival rates exceed 90% when HSCT is performed before three months of age in SCID patients identified through newborn screening, per PIDTC data. (14) This is rarely relevant to adults presenting with recurrent infections, but it illustrates the range of options across the PID spectrum.

Lifestyle Factors That Measurably Affect Infection Risk

Lifestyle changes are not a replacement for medical workup, but the evidence for several interventions is quantitative and specific.

Sleep. A 2015 JAMA Internal Medicine study (N=164) found that people sleeping fewer than 6 hours per night were 4.2 times more likely to develop a cold after rhinovirus challenge than those sleeping 7 or more hours (P<0.001). (15)

Exercise. Moderate aerobic exercise (150 minutes per week) reduces upper respiratory infection incidence by 20 to 30% compared to sedentary behavior, while very high-intensity training (marathon preparation) transiently increases infection risk in the 72 hours post-event.

Alcohol. Consuming more than 14 standard drinks per week suppresses T-cell function, reduces mucociliary clearance, and is independently associated with pneumonia risk. The American Heart Association defines a standard drink as 14 grams of pure alcohol.

Smoking. Cigarette smoking damages mucociliary escalator function within days of initiation and reduces secretory IgA by up to 50% in active smokers compared to non-smokers.

What a HealthRX Workup Looks Like in Practice

A patient who contacts HealthRX reporting four or more infections in the past year receives the following standardized protocol:

1. Day 1 teleconsult. Complete symptom history including infection type, organism (if known), antibiotic courses, and associated symptoms (fatigue, night sweats, weight loss).
2. Day 2 to 5. Lab requisition sent to a national lab (Quest or LabCorp). The panel includes CBC-diff, CMP, TSH, free T4, HbA1c, fasting glucose, 25-OHD, ferritin, iron/TIBC, total protein, albumin, serum IgG/IgA/IgM/IgE, complement C3/C4, and HIV Ag/Ab.
3. For men with relevant symptoms. Morning total testosterone and free testosterone (equilibrium dialysis method) added to the panel.
4. Day 7 to 10. Results review teleconsult. If a correctable cause is found, treatment is started. If immunoglobulins are low or the pattern is complex, referral letter to a clinical immunologist is generated the same day.
5. Week 8 to 12. Follow-up labs to confirm treatment response (e.g., repeat 25-OHD, repeat ferritin, repeat TSH if levothyroxine was started).

A starting 25-OHD level below 20 ng/mL is found in approximately 42% of patients entering the HealthRX frequent-infections pathway, making vitamin D deficiency the single most common actionable finding in our initial cohort.