Recurrent Fever, Immune Deficiency, and Autoinflammatory Disorders

History

The history must determine the frequency of fevers, associated symptoms, presence of an infection, and whether the patient returns to a normal state of health in between these episodes. Resolution of fever but persistence of other symptoms or lab abnormalities (e.g., anemia, ESR, CRP) should raise the possibility of autoimmune disease or malignancy. Regarding recurrent fevers with infections, the clinician must determine (1) the frequency, location, severity, and complications of the infections; (2) the accuracy of how infections were documented; (3) the presence or absence of a symptom-free interval; (4) the microbiologic features of any isolate; and (5) the response to antibiotic therapy. A single chronic infection may wax and wane with intermittent, inadequate treatment and may manifest as a series of infections. Furthermore, a detailed history can elucidate other risk factors for recurrent infections. Many nonimmune disorders are characterized by an increased susceptibility to infection that must also be considered ( Table 54.1 ). Approximately 30% of children with recurrent sinopulmonary symptoms can be categorized as atopic (genetic predisposition to develop allergic diseases). These subjects have normal growth and development, and episodes of recurrent illness may be afebrile, respond poorly to antibiotics, and be accompanied by upper respiratory symptoms such as coughing, sneezing, or wheezing. There may be a family history of atopic disease, and the patient’s past medical history may include episodic wheezing, protracted cough after upper respiratory tract infection (URI), hay fever, allergies to foods, or eczema. The physical examination of allergic school-aged children may reveal typical characteristics including the following: dark circles under the eyes; open mouth with dry lips; coated tongue; evidence of nasal obstruction; transverse nasal crease; boggy, pale nasal mucosa; mucus in the pharynx; posterior pharyngeal “cobblestoning”; and postnasal drip.

Malnutrition and specific vitamin deficiencies may alter immune cell function. Protein-losing states due to gastrointestinal (e.g., inflammatory bowel disease, protein-losing enteropathy) or renal disease (e.g., nephrotic syndrome) may lead to hypocomplementemia, hypogammaglobulinemia, and recurrent infections. Chronic treatment with corticosteroids and other immunosuppressants can result in acquired immunodeficiency with hypogammaglobulinemia, lymphopenia, and recurrent infections.

Perinatal History

The clinician should determine if there was exposure to maternal viral infection during gestation (HIV, cytomegalovirus [CMV], herpes simplex virus, rubella) or a history of prematurity, blood transfusions, respiratory distress syndrome, or other pertinent neonatal illnesses. Infants previously placed on ventilators may develop chronic obstructive lung disease (bronchopulmonary dysplasia), predisposing them to recurrent pulmonary infections. Most perinatal HIV infections are seen in children whose mother or mother’s partner has engaged in high-risk behavior (i.e., multiple sex partners or use of intravenous drugs). Attention should be paid to the time of umbilical cord separation since infants with a history of delayed umbilical cord separation and recurrent episodes of sepsis or pneumonia should be evaluated for leukocyte adhesion deficiency .

Anatomic Abnormalities

Recurrent infections in primary immune deficiencies typically affect different anatomic locations. Structural or anatomic defects often result in recurrent infections that are generally localized to the affected organ system. Approximately 10% of children with recurrent infections have an underlying chronic disease or a structural defect that predisposes them to recurrent infections (see Table 54.1 ).

Eustachian tube abnormalities or cleft palate results in recurrent or chronic otitis media; congenital heart disease results in an increased risk of endocarditis; and posterior urethral valves, vesicoureteral reflux, or ureteral pelvic junction obstruction results in recurrent urinary tract infections. Recurrent pneumonia may result from congenital malformations (trachea-esophageal fistulas, cystic adenomatoid malformation, or sequestration), from aspiration of a foreign body (peanut, small toys) or chronic aspiration (gastroesophageal reflux, swallowing disorders, neurologic diseases), and from bronchopulmonary dysplasia. Repeated pneumonias in dependent lobes warrant evaluation for recurrent aspiration. Chronic illnesses that result in recurrent pulmonary infections include cystic fibrosis, primary ciliary dyskinesia, or α ₁ -antitrypsin deficiency. Recurrent sinus infections can occur due to anatomic defects of the sinuses (polyps, stenotic os). Endotracheal intubation predisposes the patient to recurrent pulmonary infections with nosocomial organisms. Right middle lobe syndrome and sequestered lung can appear as recurrent pneumonia in the same anatomic location.

Any direct communication to the cerebrospinal fluid that bypasses the blood-brain barrier predisposes patients to a central nervous system infection. Basilar skull fractures and dermal sinus tracts or fistulas may communicate with the subarachnoid space or neural tissue. Other conditions predisposing patients to opportunistic infections of the central nervous system include penetrating foreign body, cerebrospinal fluid shunts, myelomeningocele, and encephalocele. Local infections of the sinuses or of the middle ear may spread to contiguous structures to form cerebral abscesses or subdural-epidural empyema. Intravenous drug use, bacterial endocarditis, and heart disease with right-to-left shunt are associated with an increased risk of central nervous system infections.

Family History

Specific patterns of inheritance have been determined for a variety of immunologic defects resulting in immune deficiency or autoinflammatory disorder. Genetic defects of immunity can be inherited as X-linked, autosomal recessive, or autosomal dominant disorders. Monogenic primary immunodeficiencies and autoinflammatory disorders may exhibit reduced penetrance (some people with the genetic abnormality do not exhibit a clinical phenotype) and variable expressivity (different signs and symptoms with the same genetic defect). A family history of unexplained infant deaths or serious infection should be sought, particularly in male infants since a number of important immune deficiencies are X-linked. Evidence of consanguinity should also be established as many serious primary immune deficiencies are autosomal recessive. Since allergic diseases can appear as recurrent infections, a family history of atopy is important. A child who has one allergic parent or two allergic parents will develop an atopic disease in 25% and 50% of cases, respectively. Some autoinflammatory disorders are more prevalent in subjects from certain geographic regions (e.g., familial Mediterranean fever), and many have an autosomal dominant inheritance pattern, and therefore a family history of fevers should be sought.

Environmental History

Respiratory and dermatologic findings are a result of exposure to environmental allergens and toxins. Specific bacteriologic and parasitic exposures are associated with certain pets (i.e., Salmonella organisms and iguanas or turtles; psittacosis and birds; Bartonella organisms in kittens). A travel history may suggest exposure to unusual organisms that are regionally endemic, such as certain parasites and specific insect or animal bites, or to contaminated water. A move to a new house or to a new nursery school or exposure to a new babysitter, pet, or housekeeper may suggest possible allergic and infectious risks.

Physical Examination

The physical examination may provide important clues to the diagnosis of a primary immune deficiency or autoinflammatory disorder. Longitudinal evaluation of height and weight is crucial in identifying infants with failure to thrive or acute weight loss. Some immune deficiencies are associated with skeletal dysplasia or growth deficiency in addition to failure to thrive. Chronic upper respiratory infections are suggested by scarred tympanic membranes, postnasal drip, and cervical adenopathy. Transverse nasal creases, circles under the eyes, and posterior pharyngeal “cobblestoning” suggest respiratory allergy. Recurrent cough, wheezing, digital clubbing, and chest deformity are suggestive of pulmonary disease. Recurrent aphthous stomatitis can be a sign of a serious systemic disorder such as immune deficiency, an autoinflammatory disorder, autoimmunity, or inflammatory bowel disease. Auscultation of the apex of the heart in the right side of the thorax (dextrocardia) may be accompanied by ciliary motility abnormalities or asplenia. Lymphadenopathy, hepatosplenomegaly, pallor, wasting, and recent weight loss are suggestive of systemic disease. Absence of lymph tissue (tonsils and lymph nodes) is suggestive of a B-cell deficiency, while absence of thymic tissue on chest radiograph in an infant is suggestive of T-cell deficiency. Parotid enlargement with lymphadenopathy and hepatosplenomegaly is suggestive of HIV infection. Skin abnormalities including alopecia, eczema, pyoderma, pustules, livedo, and telangiectasia can be important clues to immunodeficiency or autoinflammatory disorders. Evidence of hematologic disease, such as pallor, petechiae, and jaundice, can be associated with immunodeficiencies. Generalized lymphadenopathy and splenomegaly may be suggestive of HIV disease, a phagocyte disorder with recurrent infections, or a lymphoproliferative disorder.

Diagnostic Categories

The information obtained from the history and physical examination is usually sufficient to make a tentative classification:

• • The patient who is probably healthy

  • The atopic or allergic patient

  • The patient with a nonimmunologic defect in host defense

  • The patient with hereditary autoinflammatory or fever syndrome

  • The patient with a primary immunodeficiency

  • The patient with an immune disregulation disorder

The Patient Who Is Probably Healthy

Many healthy children have repeated minor infections or have a relatively brief history of repeated infections or a single prolonged illness from which recovery has been delayed. Most URIs last <7 days, and duration of >14 days is unusual. Most children younger than 1 year who have a large family or who attend daycare develop respiratory or gastrointestinal infections about 6 times during the first year of life. The onset of the recurrent infection may coincide with entry into daycare, preschool, or kindergarten. The healthy child has normal growth and development before the illness and usually a normal physical examination finding. When a discrepancy exists between the severity of an illness as reported by the parent and the child’s physical appearance, it is often prudent to delay a detailed evaluation until more objective findings are documented by repeat examinations during acute episodes. Laboratory testing might include a CBC, inflammatory markers (i.e., ESR, CRP) to exclude rheumatic disorders or occult infections, and measurement of serum immunoglobulin levels (IgG, IgA, IgM, IgE) and vaccine-specific titers as a screen. Cultures and imaging of the affected area may provide additional data. With reassurance of the parents, these children recover spontaneously. Simple measures, rather than a complex set of laboratory studies, are often the only treatment required.

Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is caused by variants in the MEFV gene that encodes the protein pyrin (see Table 54.2 ). Although FMF is considered an autosomal recessive disorder, a substantial percentage of patients with clinical FMF have only one demonstrable variant in MEFV . FMF is characterized by short episodes of fever (i.e., 1–3 days), serositis/peritonitis, prominent arthritis, and erythematous rash ( Fig. 54.1 ). Early in life fever may be the only symptom. More classic features typically appear within 3 years. The arthritis is typically monoarticular, and aspirates of affected joints are sterile with a predominance of neutrophils. In some cases, splenomegaly and systemic vasculitis can ensue. The most serious long-term comorbidity with FMF is amyloidosis, which occurs frequently in patients who are not compliant with colchicine prophylaxis. Pyrin interacts with the inflammasome, a macromolecular complex involved in the processing of interleukin-1β (IL-1β), and variants that result in FMF result in greater IL-1 production. Daily colchicine prophylaxis prevents many of the long-term complications of this disorder.

Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne Syndrome

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) is an autosomal dominant inherited syndrome caused by variants in PSTPIP1 (see Table 54.2 ), which leads to hyperphosphorylation of PSTPIP1 and increased interaction with pyrin, leading to increased IL-1β production. PAPA begins in childhood with episodes of sterile monoarticular arthritis, and later in life pyoderma gangrenosum–like ulcerative skin lesions and cystic acne ( Fig. 54.2 ). The episodes of arthritis are the most common presentation, start in early childhood, and typically affect one to three joints at a time. The joint effusions are typically neutrophil-rich and sterile. Treatment of the arthritis with surgical drainage or treatment with intraarticular or systemic steroids has shown benefit in resolving arthritis. Several reports demonstrated successful treatment with an IL-1 receptor antagonist (anakinra) or other IL-1 blockers (rilonacept, canakinumab).

Cryopyrin-Associated Periodic Syndromes

Cryopyrin-associated periodic syndromes (CAPSs) are a spectrum of autoinflammatory disorders that are inherited in an autosomal dominant manner due to variants in the NLRP3 gene (see Table 54.2 ). NLRP3 encodes cryopyrin, a protein that is part of the inflammasome. Variants that cause CAPS prevent autoinhibition of the cryopyrin protein, resulting in spontaneous activation of the inflammasome and excessive production of IL-1β.

CAPS consists of three diseases: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID), which represent a spectrum of disorders that present with recurrent or continual systemic inflammation, rash, fevers, arthritis, neurologic deficits, and amyloidosis. FCAS is the mildest form of this disorder that presents with fevers, an evanescent rash, headache, conjunctivitis, and joint pain after generalized cold exposure. Although the rash can have some visual features of urticaria, it is macular without signs of mast cell degranulation, and is histologically characterized by a neutrophilic infiltrate. MWS presents similarly to FCAS, but cold exposure is not necessary for symptoms to occur ( Fig. 54.3 ). Unlike FCAS, chronic meningitis occurs with papilledema and sensorineural hearing loss, joint pain and swelling is more severe, and untreated, amyloidosis develops over time. NOMID is the most severe variant of CAPS. Like MWS, all patients with NOMID exhibit a rash at or shortly after birth ( Fig. 54.4 ). Neurologic symptoms, such as aseptic meningitis, headache, cerebral atrophy, uveitis, hearing loss, and intellectual disability, are common and severe. In NOMID and MWS, chronic inflammation of the joints leads to a chronic arthropathy with epiphyseal and patellar overgrowth. FCAS, MWS, and NOMID exhibit laboratory evidence of an acute-phase response with leukocytosis, neutrophilia, anemia, thrombocytosis, and elevated ESR and CRP levels.

IL-1 inhibitors (anakinra, rilonacept, canakinumab) are now the treatment of choice for these disorders based on their ability to induce rapid and sustained clinical response. Laboratory abnormalities typically normalize in days, and the rash responds rapidly. Importantly, IL-1 blockade improves long-term morbidity such as hearing loss, joint deformity, and amyloidosis.

Hyperimmunoglobulin D Syndrome

Hyperimmunoglobulin D syndrome (HIDS) is an autoinflammatory disorder caused by variants in the mevalonate kinase (MVK) gene (see Table 54.2 ). MVK is an enzyme involved in the biosynthesis of cholesterol and isoprenoids. Patients with HIDS have low but detectable MVK enzyme activity resulting in elevated levels of mevalonic acid in the urine, particularly during attacks. Complete absence of MVK results in mevalonic aciduria, an inborn error of metabolism, which is also associated with fevers. It is unclear how variants in MVK lead to an autoinflammatory disease.

The clinical manifestations of HIDS occur at an early age with recurrent fevers with lymphadenopathy, abdominal pain, arthralgia and arthritis, and painful migratory erythematous macules. These episodes may last 4–7 days and are often triggered by stress, trauma, or vaccination. Serum IgD and IgA levels are usually elevated but may be normal. Acute-phase reactants are elevated during attacks. Although high-dose corticosteroids and tumor necrosis factor-α (TNF-α) antagonists have been used with variable success, IL-1β inhibitors appear more effective at preventing the inflammatory episodes. Amyloidosis may occur but is relatively rare.

Deficiency of the Interleukin-1 Receptor Antagonist

Deficiency of the IL-1 receptor antagonist (DIRA) is an autosomal recessive disorder due to variants in the IL-1 receptor antagonist gene (IL-1RN) (see Table 54.2 ). IL-1 receptor antagonist (IL-1RA) is a decoy protein that binds to the IL-1 receptor but does not result in signaling, and the absence of IL-1RA in patients with DIRA leads to cellular hyperresponsiveness to IL-1β.

The clinical manifestations of DIRA occur within the first 2 weeks of life and include pustular rash, osteopenia, lytic bone lesions, and prominent systemic inflammation. All patients develop cutaneous pustulosis, and biopsies of the skin lesions revealed a neutrophilic predominance ( Fig. 54.5 ). Respiratory distress, aphthous ulcers, hepatomegaly, and failure to thrive occur, with approximately one-third of infants expiring prior to diagnosis and effective treatment. Bone is prominently involved, with osteopenia, multiple osteolytic lesions, and rib widening. Laboratory abnormalities reflect an acute-phase response with elevated ESR and CRP, leukocytosis, anemia, and thrombocytosis.

Anakinra, a recombinant IL-1RA, is highly effective in the treatment of DIRA. Anakinra essentially replaces the IL-1RA that patients with DIRA cannot synthesize. The longer-acting anti–IL-1 agents canakinumab and rilonacept also work with the advantage of less frequent dosing compared to anakinra but are considerably more expensive.

TNF Receptor–Associated Periodic Syndrome

TNF receptor–associated periodic syndrome (TRAPS) is an autosomal dominant disease associated with missense variants in the extracellular domain of the TNF receptor 1 (TNFR1) gene (TNFRSF1A) (see Table 54.2 ). The clinical manifestations of TRAPS include recurrent and often prolonged fevers, abdominal pain, and arthralgias. A migratory rash with underlying fascial inflammation and myalgia can be seen, as well as conjunctivitis and periorbital edema ( Fig. 54.6 ). Increased serum levels of CRP, ESR, leukocytosis, and thrombocytosis are evident during and in between attacks. Initial insights into the pathophysiology of this disorder came when patients with TRAPS exhibited low serum levels of soluble TNFR1, suggesting that shedding of TNF receptors acts as a natural antagonist to TNF-α. In support of this, the TNF-α antagonist etanercept has been shown to reduce the severity of symptoms in some cases of TRAPS. However, not all patients with TRAPS have low serum TNFR1 levels, and TNF-α inhibition is not completely effective. Reports have also shown the beneficial effects of IL-1 inhibition and the anti–IL-6 receptor antibody tocilizumab.

Deficiency of Adenosine Deaminase 2

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disorder due to loss of function of CECR1 , which encodes adenosine deaminase 2 (ADA2) (see Table 54.2 ). The clinical manifestations of DADA2 begin in childhood with intermittent fevers, recurrent lacunar strokes, organomegaly, hypogammaglobulinemia, and systemic vasculitides. Pure red cell aplasia, immune thrombocytopenia, neutropenia, and bone marrow failure have been observed. The lacunar strokes begin before the age of 5 years and typically occur during inflammatory episodes. A livedo-like rash is a prominent feature with biopsies showing a predominance of neutrophils and macrophages as well as vasculitis in medium-sized vessels. Some of these patients are diagnosed with early-onset polyarteritis nodosa. Treatment with glucocorticoids, TNF-α inhibitors, and IL-1 blockers has been utilized with some benefit. Hematopoietic stem cell transplantation is increasingly the treatment of choice for this disorder.

Interferonopathies

Another group of disorders that result in spontaneous inflammation are known as interferonopathies ( Fig. 54.7 and Table 54.4 ). Interferonopathies are genetic defects that result in the spontaneous production of type 1 interferons, which leads to inflammation and characteristic features. The genetic defects occur in genes that process or detect intracellular nucleic acids, a sign of viral infections, resulting in the production of type 1 interferon and subsequent systemic inflammation. Since interferons signal through Janus kinases, which results in inflammation, targeted therapies with Janus kinase inhibitors have shown promise.

STING-Associated Vasculopathy

STING-associated vasculopathy of infancy (SAVI) is an autoinflammatory disorder that presents with intermittent low-grade fevers; rashes on the cheeks, nose, or digits; myositis; arthritis; and evidence of interstitial lung disease (see Table 54.2 ). The vascular involvement can be significant resulting in ulceration of the distal extremities with tissue infarcts ( Fig. 54.8 ). Autosomal dominantly inherited variants in the signaling molecule STING, which senses altered intracytoplasmic double-stranded DNA levels, lead to its spontaneous activation and the production of type 1 interferon. Currently there is no treatment, although Janus kinase inhibitors are available based on in vitro studies and case reports.

Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature

Misfolded or damaged proteins are degraded by the proteasome, and defects in the proteasome lead to buildup of dysfunctional or misfolded proteins. This buildup occurs during viral infections and is sensed by the cell with resultant interferon production. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) occurs due to genetic defects in the proteasome with resultant type 1 interferon production (see Table 54.2 ). Mild infections, cold, or stress affects metabolic demands, which can precipitate episodes of inflammation in this disorder. Features include early-onset recurrent fevers; rashes on the fingers, toes, face, and ears; and erythematous or violaceous periorbital and perioral edema. Erythematous nodules, plaques, and purpuric lesions can occur, and biopsies demonstrate leukocytoclastic vasculitis with fibrinoid necrosis and panniculitis. Labs are significant for elevated inflammatory markers, chronic anemia, thrombocytosis, and hypergammaglobulinemia. Over time lipodystrophy, aseptic meningitis, and synovitis develop. Autosomal recessive loss-of-function variants in the PSMB8 gene, which codes for the proteasome subunit β5i, is the classic defect, but genetic variants in the other subunits of the proteasome may also result in CANDLE syndrome.

NF-κB Related Disorders

Nuclear factor-κB (NF-κB) family members are sequestered in the cytoplasm bound to inhibitory proteins, and when activated these proteins are degraded via the ubiquitin pathway, allowing for the nuclear translocation of NF-κB and the transcription of many inflammatory proteins. De-ubiquitinating enzymes inhibit this process, and genetic variants in two of these proteins, otulin and A20, lead to autoinflammatory disorders. Otulipenia , due to homozygous loss-of-function variants in the FAM105B gene that encode otulin, may present with episodes of recurrent fevers, joint swelling, painful nodular red rash, gastrointestinal inflammation with diarrhea, and failure to thrive. Biopsies of the rash will show a neutrophilic dermatosis and small/medium-vessel vasculitis. A20 haploinsufficiency is an autosomal dominantly inherited autoinflammatory disorder caused by genetic variants in the TNFAIP3 gene (see Table 54.2 ). Patients present with systemic inflammation, oral and genital ulcers, uveitis, and fevers similar to familial Behçet disease. Other autoinflammatory disorders, such as Blau syndrome, have also been postulated to lead to NF-κB activation. Blau syndrome is an autosomal dominant disease caused by variants in NOD2 that result in spontaneous activation of the NOD2 protein, activation of NF-κB, and production of proinflammatory cytokines. Blau syndrome was originally described as a granulomatous disease affecting the skin, joints, and uveal tract and should be considered in any individual presenting with early-onset sarcoidosis. Blau syndrome presents with a boggy synovitis of large joints, particularly the wrists and ankles, and an erythematous papular rash similar to erythema nodosum. Biopsy of these lesions demonstrates noncaseating granulomas. Unlike sarcoidosis, respiratory involvement and hilar adenopathy are rare, although granulomatous liver disease, cranial neuropathies, and large-vessel vasculitis can occur. Laboratory studies in Blau syndrome are typically normal, although elevated ESR and angiotensin-converting enzyme levels can be seen, and hypergammaglobulinemia can occur. Most patients with Blau syndrome have been treated with corticosteroids, although limited reports have shown effectiveness of infliximab, thalidomide, and possibly anakinra.