Recurring Upper Respiratory Infections

Patients with innate immune deficiencies frequently report repeated respiratory tract infections, including:

• Colds

• Influenza

• Bronchitis

• Otitis media - ear infections 

• Post-infectious cough [52][56].

Neutrophils, being the most abundant innate effector cells, are essential for clearing pyogenic bacteria like Streptococcus pneumoniae and Haemophilus influenzae. Inadequate neutrophil recruitment or function results in delayed bacterial clearance, prolonged inflammatory damage and exacerbation of infection [52][56].

Furthermore, Macrophages contribute by orchestrating both the initiation and resolution of inflammation. Their impaired function can lead to persistent cytokine elevation, ineffective phagocytosis, and immune exhaustion, which contributes to chronic infection cycles [27].

Respiratory Infection Recovering time > 10 days

Following an upper respiratory tract infection, symptoms such as sore throat, nasal congestion, and running sinuses typically resolve within seven to ten days, though a cough may persist for several weeks due to lingering airway sensitivity. 

When nasal or systemic symptoms extend beyond this expected recovery window, it indicates underlying immune impairment. In particular, persistent colds beyond 10 - 14 days may indicate compromised innate immune function, as effective clearance of viral pathogens depends heavily on the activity of neutrophils and macrophages. [75] 

Respiratory Infection Symptom Relapse 

A clinical scenario in which upper respiratory tract infection symptoms improve initially but then worsen again is suggestive of impaired neutrophil and macrophage activity. This relapse pattern often reflects an inability of the innate immune system to fully eradicate pathogens, predisposing to secondary bacterial infections or prolonged viral replication. [75]

Chronic Sinusitis

Sinusitis is the inflammation or infection of the sinuses around the nose and eyes. It usually happens when the drainage pathways of the sinuses become blocked. It can present as the following:

• Nasal congestion or blockage

• Nasal discharge

• Facial pressure when bending forward

• Reduced sense of smell

• Headaches

• Bad breath

Chronic or recurrent sinusitis is a hallmark symptom of impaired neutrophil activity. Neutrophils are responsible for rapid response to microbial invasion of the respiratory tract. They eliminate pathogens via phagocytosis, release of antimicrobial peptides, and formation of neutrophil extracellular traps (NETs). 

In impaired neutrophil states either numerical or functional, the sinus mucosa is unable to clear pathogens efficiently, resulting in chronic bacterial colonization, mucosal thickening, and secondary fungal overgrowth [33]. Furthermore, Macrophages in the sinonasal mucosa are key to epithelial repair and maintaining immune surveillance. A failure in macrophage polarization toward a tissue-reparative (M2) phenotype contributes to chronic inflammation, tissue remodeling and persistent infection [26].

Recurring Candida [ Candidiasis ]  

Infections of the pathogenic yeast candida albicans occurs more frequently in individuals with innate immune deficiencies. Neutrophils play a pivotal role in fungal clearance by producing reactive oxygen species and through degranulation. Reduced neutrophil oxidative burst or delayed recruitment to mucosal surfaces permits fungal colonization [52].

Furthermore Macrophages produce cytokines that amplify the antifungal response and help in antigen presentation. Dysfunctional macrophages lead to an insufficient immune signal, allowing Candida proliferation even under antifungal treatment [33].

Chronic Fungal Skin Infections

• Tinea pedis - athlete’s foot

• Tinea cruris - jock itch

• Tinea corporis - Ringworm 

• Tinea versicolor - Pityriasis versicolor 

• Malassezia yeast  - Dandruff

Within the innate immune system, specialized receptors found on innate immune cells like macrophages and dendritic cells are responsible for detecting structural components of fungal cell walls, triggering immune responses via signaling pathways. 

In instances where the fungal recognition system is impaired due to immune suppression, these cells fail to produce signals, which normally help recruit and activate other immune cells. Therefore the performance of two essential innate immune cells: neutrophils and macrophages is impaired, allowing dermatophyte fungi to persist, leading to recurrent or chronic fungal infections [72].

Chronic Bacterial Infections

• Urinary Tract Infections - Urination burning, frequency or urgency

• Abscess – Red, swollen, pus-filled skin lump.

• Cellulitis – Red, warm, tender skin

• Folliculitis – Small, red, pus-topped hair bumps

• Paronychia - swelling of the nail bed

Neutrophils are the primary defence cell, responsible for rapid microbial clearance at sites of injury. Impairments in neutrophil signalling and overall capacity result in inadequate pathogen elimination, prolonged inflammation, and an increased risk of recurrent bacterial infections [23]. Furthermore, macrophages, particularly dermal macrophages, play an equally important role in clearing cellular debris, orchestrating inflammatory resolution, and remodelling damaged tissue. Dysfunction in macrophage activation or polarisation can lead to persistent epithelial damage and inflammation.

Clinically, patients with defects in innate immunity often present with a spectrum of manifestations, ranging from recurrent UTI's to superficial pustules and boils to more invasive cellulitis and deep abscess formation. They may also exhibit delayed wound healing, chronic ulcerations, or unusual colonization on the epithelial  cells. [23][33].

Chronic Acne

Neutrophils and macrophages play essential roles in the skin's immune defense, particularly in responding to Cutibacterium acnes, the bacterium central to acne pathogenesis, and their impairment can significantly exacerbate acne. 

When functioning normally, macrophages detect C. acnes through pattern recognition receptors, triggering the release of cytokines, which recruit neutrophils to the site of infection. Neutrophils, in turn, carry out antimicrobial actions, including phagocytosis, degranulation, and oxidative bursts. 

However, when neutrophils or macrophages are deficient or functionally impaired, due to poor chemotaxis, reduced cytokine production, inadequate phagocytic ability, or diminished reactive oxygen species output, the immune response becomes insufficient, allowing C. acnes to persist and inflammation to escalate [60].

Recurring Herpes Simplex Virus 

• Coldsores

• Gentital Herpes

Lymphocytes, especially T-cells, are the main part of the immune system that keeps herpes simplex virus (HSV) under control after the first infection. Once HSV settles into the nerve cells and becomes “latent,” the body relies on the lymphocyte subset - CD8⁺ T-cells to sit near those nerves and constantly monitor the virus, stopping it from waking up and multiplying. Whereas lymphocyte subset CD4⁺ T-cells help by supporting and strengthening this antiviral response. [76]

When these lymphocytes are low in number or not working well, this protective surveillance weakens. As a result, HSV has an easier time reactivating, which leads to more frequent cold sores or genital outbreaks, more viral shedding, and slower healing. [76]

Post Infectious Fatigue 

When neutrophils are impaired, they fail to effectively eliminate pathogens, contributing to low-grade, persistent inflammation post-infection. Likewise, when macrophages are unable to properly clear dying neutrophils, a process known as efferocytosis, cellular debris accumulates, further amplifying the inflammatory response and hindering resolution [27][33]. Patients with innate immune dysfunction often report that fatigue worsens after minor infections as a result of immune over-activation with inadequate resolution [33].

Wound Infections and Poor Healing

Poor wound healing is a direct consequence of disruptions in the innate immune system's orchestrated tissue repair process. It involves two major phases regulated by neutrophils and macrophages:

Neutrophils are the initial cellular responders to injury. They migrate rapidly to the wound site, clear pathogens and cellular debris via phagocytosis and release proteolytic enzymes and reactive oxygen species to sterilize the wound bed. In cases of innate immune impairment, this early clearance phase is compromised. The wound remains vulnerable to infection, and debris accumulates, impairing downstream repair [53]. 

Macrophages on the other hand transition from a pro-inflammatory early stage, to an anti-inflammatory repair stage. Their critical roles include tissue regeneration, recruitment and activation of fibroblasts and keratinocytes for collagen deposition and re-epithelialization.
Impairments in these processes delays the transition to tissue repair and prolongs healing [27].