**7. Clinical presentation**

Symptoms of patients with XLA most often begin at about 6 to 9 months of age, when the transferred maternal immunoglobulin has been catabolized and the infant becomes dependent on his own immune system. Widespread use of antibiotics may often mask the presentation of disease and despite recurrent sinopulmonary infections diagnosis of XLA may delay until 3–5 years of age or adolescence in some cases [8]. In a small subpopulation of cases with XLA, about 10% to 15%, who are not recognized to have immunodeficiency until 5 years of age, serum immunoglobulin levels may be high [46]. Patients with XLA are clinically characterized by an onset of recurrent bacterial infections due to remarkable decrease in immunoglobulin levels [5–9, 47–50].

The clinical findings leading to the diagnosis of XLA were determined in 82 patients with proven mutations in Bruton's tyrosine kinase. The authors reported that the majority of patients with XLA had a history of recurrent otitis at the time of diagnosis. The physical findings of decreased or absent tonsils and cervical lymph nodes could have alerted physicians to the diagnosis of XLA [51].

Clinical presentations of X-linked agammaglobulinemia have been defined by a multicenter retrospective survey of 96 patients. The onset of infections was in the first 4 months of life (25% of cases), 8 months of life (50% of cases), 12 months of life (75% of cases), and 18 months of life (90% of cases). The most frequent infections involved the upper respiratory tract (75%), the lower respiratory tract (65%), the gastrointestinal tract (35%), the skin (28%), and the central nervous system (16%) [52].

Infection usually develops at the surface of mucous membranes, namely, middle ear, sinuses, and lungs. Pneumonia, otitis media, sinusitis, conjunctivitis, and diarrhea are the hallmark of XLA patients. In some cases, infection can spread through the bloodstream, and septicemia, meningitis, septic arthritis, cellulitis, and osteomyelitis may occur. *S. pneumoniae* and *H. influenzae* are the most common responsible encapsulated pathogens of infections. These microorganisms also affect all patients with antibody deficiency, such as common variable immunodeficiency (CVID); however, patients with XLA have susceptibility to enteroviral infection in contrast to other antibody deficiencies.

There are many published data about the clinical presentation of XLA. They are reflecting the results of different population of XLA patients. The frequency of clinical presentations is variable due to different cohorts of XLA patients assessed.

Infection was the most common initial clinical presentation (85%), followed by a positive family history (41%) and neutropenia (11%) in 201 XLA patients included in the United States Registry. The average age of diagnosis was significantly younger in patients with a positive family history (2.59 years) than in patients with a negative family history (5.37 years) (*p* < 0.001). Seventy percent of patients had at least 1 episode of otitis, 62% at least 1 episode of pneumonia, 60% at least 1 episode of sinusitis, 23% at least 1 episode of chronic/recurrent diarrhea, 21% at least 1 episode of conjunctivitis, 18% at least 1 episode of pyoderma and/or cellulitis, 11% at least 1 episode of meningitis/encephalitis, 10% at least 1 episode of sepsis, 8% at least 1 episode of septic arthritis, 6% at least 1 episode of hepatitis, and 3% at least 1 episode of osteomyelitis. Of 201 patients, 14 (6.9%) were dead at the time they were entered in the registry. Causes of death were disseminated enterovirus infection (*n* = 6), pulmonary insufficiency (*n* = 5), adenovirus infection (*n* = 1), sepsis (*n* = 1), acquired immunodeficiency disease syndrome (AIDS) (*n* = 1), myocarditis (*n* = 1), hepatitis (*n* = 2), and stem cell transplantation (*n* = 1) [53].

**7. Clinical presentation**

224 Immunopathology and Immunomodulation

levels [5–9, 47–50].

to the diagnosis of XLA [51].

nervous system (16%) [52].

infection in contrast to other antibody deficiencies.

variable due to different cohorts of XLA patients assessed.

Symptoms of patients with XLA most often begin at about 6 to 9 months of age, when the transferred maternal immunoglobulin has been catabolized and the infant becomes dependent on his own immune system. Widespread use of antibiotics may often mask the presentation of disease and despite recurrent sinopulmonary infections diagnosis of XLA may delay until 3–5 years of age or adolescence in some cases [8]. In a small subpopulation of cases with XLA, about 10% to 15%, who are not recognized to have immunodeficiency until 5 years of age, serum immunoglobulin levels may be high [46]. Patients with XLA are clinically characterized by an onset of recurrent bacterial infections due to remarkable decrease in immunoglobulin

The clinical findings leading to the diagnosis of XLA were determined in 82 patients with proven mutations in Bruton's tyrosine kinase. The authors reported that the majority of patients with XLA had a history of recurrent otitis at the time of diagnosis. The physical findings of decreased or absent tonsils and cervical lymph nodes could have alerted physicians

Clinical presentations of X-linked agammaglobulinemia have been defined by a multicenter retrospective survey of 96 patients. The onset of infections was in the first 4 months of life (25% of cases), 8 months of life (50% of cases), 12 months of life (75% of cases), and 18 months of life (90% of cases). The most frequent infections involved the upper respiratory tract (75%), the lower respiratory tract (65%), the gastrointestinal tract (35%), the skin (28%), and the central

Infection usually develops at the surface of mucous membranes, namely, middle ear, sinuses, and lungs. Pneumonia, otitis media, sinusitis, conjunctivitis, and diarrhea are the hallmark of XLA patients. In some cases, infection can spread through the bloodstream, and septicemia, meningitis, septic arthritis, cellulitis, and osteomyelitis may occur. *S. pneumoniae* and *H. influenzae* are the most common responsible encapsulated pathogens of infections. These microorganisms also affect all patients with antibody deficiency, such as common variable immunodeficiency (CVID); however, patients with XLA have susceptibility to enteroviral

There are many published data about the clinical presentation of XLA. They are reflecting the results of different population of XLA patients. The frequency of clinical presentations is

Infection was the most common initial clinical presentation (85%), followed by a positive family history (41%) and neutropenia (11%) in 201 XLA patients included in the United States Registry. The average age of diagnosis was significantly younger in patients with a positive family history (2.59 years) than in patients with a negative family history (5.37 years) (*p* < 0.001). Seventy percent of patients had at least 1 episode of otitis, 62% at least 1 episode of pneumonia, 60% at least 1 episode of sinusitis, 23% at least 1 episode of chronic/recurrent diarrhea, 21% at least 1 episode of conjunctivitis, 18% at least 1 episode of pyoderma and/or cellulitis, 11% at least 1 episode of meningitis/encephalitis, 10% at least 1 episode of sepsis, 8% at least 1 episode

The median age at the onset of the disease was 8 months, and the median age of diagnosis was 48 months based on the records of 33 Iranian XLA patients. The most frequent infections were seen in the respiratory tract (93.9%), gastrointestinal tract (75.8%), central nervous system (33.3%), and musculoskeletal system (21.2%). Chronic otitis media, chronic sinusitis, chronic diarrhea, and bronchiectasis were developed complications in 75.8% of cases [54].

The mean age of onset was 2.5 years, and the mean age at diagnosis was 7.3 years in six patients with XLA from northern Thailand. Patients had a history of otitis media, pneumonia, arthritis, and sinusitis (5/6); pericarditis (1/6), meningitis (1/6), and pyoderma (1/6) were other experi‐ enced infections. *Pseudomonas aeruginosa* and *Staphylococcus aureus* were isolated on multiple occasions in five patients. Five cases had developed bronchiectasis and three patients septice‐ mia [55].

Recurrent pulmonary infections and an unusual course of common pulmonary infection should alert physician for underlying immunodeficiency. Lung infections were evaluated in 39 Iranian patients with XLA. The authors reported that 82% (32/39) of patients with XLA experienced at least one episode of pneumonia, and 84% (27/32) of those patients had more than one episode. An average rate of pneumonia episode per patient per year was 1.67 for XLA patients [56].

A patient with XLA presenting with respiratory distress, was reported to have *Pneumocystis jirovecii* pneumonia. This patient is a reminder that the potential consequences of BTK deficiency in cells other than B-cells should be considered [57].

Mycoplasma infections may involve the respiratory tract, the urogenital tract, and joints, leading to prolonged than severe course or asymptomatic in some cases [58, 59].

Skin infections such as impetigo, abscesses, and furuncles due to group A streptococcus or staphylococcus had been also reported.

Although patients with XLA experience childhood viral infections uneventful, they have susceptibility to certain viruses. Enteroviral infections (echovirus, coxsackievirus, and polio virus) frequently run a severe course and often resist therapy in affected patients. Enterovirus may cause severe and, eventually, fatal progressive encephalitis [5–9, 52, 60, 61].

Clinical manifestations of enteroviral meningoencephalitis demonstrate great variation changing from severe infection to chronic enteroviral infection. Illness may be overt as acute infection with fever, headache, and seizures or tend to progress slowly throughout the years with loss of cognitive skills, ataxia, paresthesia, neurosensory hearing loss, and lethargy [60, 61]. The laboratory assessment of cerebrospinal fluid (CSF) may reveal clear fluid, pleocytosis (<1000/mm3 ), elevated protein level (0.5–5 g/dL), and in a few cases hypoglycorrhachia or normal CSF results. Polymerase chain reaction (PCR) techniques may detect virus in CSF. Initial magnetic resonance imaging (MRI) or computed tomography (CT) scan reveal no abnormality; however, cortical or subcortical atrophy, ventricular dilatation, periventricular changes, and hydrocephaly may be observed later in life. There are no typical histopathology findings at brain biopsy. Illness is progressive and mortality is very high. As a result of disseminated enteroviral infection, dermatomyositis-like syndrome may develop with erythematous rash and peripheral edema. Hepatitis with increased alanine aminotransferase (ALT) may accompany [60–63].

Gastrointestinal disorders are common problems of XLA patients. Patients may have infec‐ tions, autoimmunity, or rarely malignancy. *Campylobacter jejuni* is the most frequent pathogen causing gastrointestinal tract infection. Typically, affected patients suffer from fever, skin rash, and persistent diarrhea [64–66]. Parasitic infection especially *Giardia lamblia* infection may cause abdominal pain, diarrhea, poor growth, or loss of serum proteins. *Giardia* can be isolated from stool samples of patients and too hard to eradicate.

Inflammatory disorders in XLA patients unexpectedly occur. A web-based patient survey was conducted in patients with XLA. Based on 128 patient responses, the majority of respondents (69%) reported having at least one inflammatory symptom. Just 28% of them had been diagnosed with an inflammatory condition. Arthritis had been diagnosed only in 7% XLA patients, despite 20% reported painful joints and 11% reported swelling of the joints. Similarly, 21% reported symptoms of chronic diarrhea and 17% reported abdominal pain. However, only 4% had been diagnosed with Crohn's disease. Data from the United States Immune Deficiency Network (USIDNET) Registry on 149 patients with XLA revealed that 12% had pain, swelling, or arthralgia, while 18% had been diagnosed with arthritis [67]. Kawasaki disease is also reported in an XLA patient, providing opportunity to understand the relationship between autoimmunity and XLA [68].

Noninfectious or infectious arthritis may occur in patients with X-linked agammaglobuline‐ mia. Juvenile rheumatoid is relatively common in patients with XLA. The mechanisms are not clear of noninfectious arthritis. *H. influenzae*, *S. pneumoniae*, and mycoplasma are pathogens causing septic arthritis. Pain and swelling of joints are presenting symptoms. Erythrocyte sedimentation rate increase, rheumatoid factor (RF), and antinuclear antibody (ANA) tests are negative. Arthritis may be the first presenting symptom of X-linked agammaglobulinemia. That is the reason why physicians must be aware of immunodeficiencies [69, 70].

Growth hormone deficiency associated with XLA patient has been reported [71].

Although the relationship between the Bruton kinase mutation and the development of malignant tumors is unknown, XLA patients seem to be at risk for colorectal cancer and lymphoid malignancies. B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been reported in a case with XLA. It has been reported that somatic mutation found in MLL2 suggests that the alterations of BTK and MLL2 synergistically function as leukemogenesis [72, 73].

Cases with vaccine-associated paralytic poliovirus infection as a consequence of attenuated oral polio (Sabin) have been reported in XLA patients [74]. The incubation period of the infection is more than 30 days, and chronic encephalomyelitis develops eventually [75].
