Peri-Operative Considerations in the Patient with Primary Immune Deficiency: A Review

Abstract

Background:

Patients with inherited immune deficiency diseases often require surgical procedures, and their immune defects may predispose them to surgical complications.

Methods:

A thorough review of pertinent literature and current practice guidelines on surgery in patients with immune deficiency.

Results:

Peri-operative infections are a key, but not a singular, consideration in managing patients with a primary immune deficiency. Bleeding diathesis, gastrointestinal complications, pulmonary complications, and poor incision healing may also be idiosyncratic features unique to particular immune deficiency diseases. Patients with complex genetic syndromes that include immune deficiency also may display non-immunologic abnormalities that are equally important to surgical care.

Conclusion:

Greater awareness of primary immune deficiencies and a comprehensive evaluation of such patients in close consultation with an immunologist can minimize surgical complications and optimize patient outcomes.

Primary immune deficiencies comprise a heterogeneous group of genetic diseases predisposing patients to be susceptible to both ordinary and exotic pathogens. Although individual disorders within this category may be rare, the combined prevalence of all primary immune deficiency diseases (1:1,200) is sufficiently high that most surgical services will encounter them with regularity [1]. Moreover, patients with primary immune deficiency diseases often require a surgical procedure; when they do, they are especially vulnerable to peri-operative and intra-operative complications [2]. This review is intended to assist surgical services with the expectant management of patients with an established primary immune deficiency diagnosis. For patients with a suspected primary immune deficiency disorder requiring a non-emergency intervention, a thorough immunologic evaluation by a qualified clinical immunologist, hematologist/oncologist, or infectious diseases physician should precede surgical action. Full recognition of the underlying immune defect can aid in anticipating surgical complications that include infections, bleeding, gastrointestinal complications, pulmonary complications, and poor incision healing.

Infections

In primary immune deficiency diseases, the specific pathogens and infected sites often are linked to the underlying immunologic defect. For example, patients with antibody deficiency, including common variable immune deficiency (CVID) and X-linked agammaglobulinemia (XLA), characteristically suffer sino-pulmonary infections with encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae (Table 1) [3]. By contrast, patients with T-cell defects, including severe combined immune deficiency (SCID), suffer repeated opportunistic infections, including cryptosporidial sclerosing cholangitis and Pneumocystis pneumonia [4]. Patients with terminal complement deficiency have an exquisite susceptibility to Neisseria meningitidis. Awareness of this epidemiology may prompt surgical teams evaluating an immune-deficient patient to consider both typical pathogens encountered in the peri-operative setting and more unusual organisms that are associated specifically with the patient's underlying immune defect.

Table 1.

Characteristic Infections in Primary Immune Deficiency Diseases

Primary Immune Deficiency	Characteristic Infections and Pathogens
Antibody deficiency diseases: CVID, XLA, other forms of hypogammaglobulinemia	Sino-pulmonary infections (Streptococcus pneumoniae, Haemophilus influenzae), giardiasis
Combined immune deficiency: SCID, CD40L deficiency	Fungal pneumonia (Pneumocystis jirovecii, Aspergillus spp.) sclerosing cholangitis (Cryptosporidium spp.), chronic diarrhea (Cryptosporidium spp., Giardia lamblia, rotavirus), central nervous system infections (echovirus, Cryptococcus), candidal esophagitis. Also, susceptibility to infections experienced by patients with antibody-deficiency diseases
Mucocutaneous candidiasis: autosomal dominant STAT3-related hyper-IgE syndrome, gain-of-function STAT1-related disease, autosomal recessive DOCK8-related hyper IgE-syndrome, APECED	Chronic mucocutaneous candidiasis, skin and soft-tissue abscesses (Staphylococcus aureus, Candida albicans), pneumonia, and pneumatocele (P. jirovecii, Aspergillus spp., S. aureus)
Defects of phagocyte function and trafficking: CGD, LAD	Pneumonia (S. aureus, Burkholderia cepacia, Serratia marcescens, Nocardia spp., Aspergillus spp.), granuloma and adenitis (S. aureus, S. marcescens) osteomyelitis (Aspergillus spp., S. marcescens)
Complement deficiency	Meningitis (Neisseria meningitidis), bacteremia (S. pneumoniae, H. influenzae, Staphylococcus spp.)
Wiskott-Aldrich syndrome	Sinopulmonary infections (S. pneumoniae, H. influenzae), bacteremia, and meningitis; viral infections (varicella, Herpes simplex)

APECED=autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; CGD=chronic granulomatous disease; CVID=common variable immune deficiency; LAD=leukocyte adhesion deficiency; SCID=severe combined immune deficiency; XLA=X-linked agammaglobulinemia.

One issue of specific practical interest to surgical teams treating patients with immune deficiencies is the prevention of and effective surveillance for post-operative infections. There is no evidence to support additional or special intra-operative/peri-operative antimicrobial prophylaxis for patients with primary immune deficiencies. We suggest that surgical teams adhere broadly to current American Society of Health-System Pharmacists (ASHP) Surgical Infection Society (SIS) guidelines regarding this issue and, so as to avoid antibiotic resistance, to choose agents that have not been administered to the patient recently [5]. Regarding monitoring patients with primary immune deficiency for postoperative infections, we recommend utilizing strategies already proved to be effective in immune-competent individuals but with a few disease-specific caveats. For instance, fever and reactive leukocytosis are durable indicators of infection in most primary immune deficiencies but are not reliable in patients with innate immune defects, including those with NEMO mutations as well as MyD88 and IRAK-4 deficiency [6]. As these patients are unable to mount a febrile response or to mobilize neutrophils, the presence of “soft” signs such as the formation of pus, malaise, or changes in hemodynamics require immediate medical evaluation. Conversely, remarkable neutrophilia (>20,000 cells/mm³) is characteristic of most well patients with leukocyte-adhesion deficiency and is not necessarily a sign of an acute infection [7]. Once an infectious process is suspected in a patient with a primary immune deficiency, the identification of the offending pathogen and that pathogen's antimicrobial susceptibilities are paramount to crafting an effective antibiotic strategy. An important diagnostic consideration particular to patients with poor adaptive immunity (B-cell and T-cell defects) is that infectious serology tests are of limited value because of the inability of these individuals to form immunologic memory. In such cases, we recommend isolation of pathogens directly by culture or using more refined molecular methods such as polymerase chain reaction.

Antibody deficiency is common in primary immune-deficiency diseases, and patients receiving immunoglobulin G (IgG) replacement therapy for infectious prophylaxis may require its administration during the peri-operative period [3]. Historically, IgG replacement has been administered monthly by the intravenous route (IVIG), although an increasing number of patients now receive weekly subcutaneous administration (SQIG). Given the half-life of IVIG (21–30 d) and the considerable interval between infusions, practitioners should expect that the serum IgG concentration in the week preceding an infusion will be only half that of the week following an infusion [8,9]. Hence, whenever possible, patients receiving IVIG replacement should be scheduled for surgical procedures, especially those involving general anesthesia or considerable blood loss, in the period immediately after an IVIG infusion. For patients using weekly SQIG, which is a depot injection that diffuses slowly into the peripheral circulation, the timing of a surgical procedure to optimize the serum IgG concentration does not require pre-operative consideration [10]. Post-operatively, serum IgG concentrations may be diminished considerably, especially if surgical blood loss was substantial or in clinical scenarios including diarrhea, nephrosis, or burns, wherein antibody is consumed or wasted [11 –15]. In such cases, the serum IgG concentration should be determined quickly post-operatively. If the value is found to be either below the institutional age-appropriate normal range (700–1,600 mg/dL at our institution) or below the lowest value acceptable by the patient's immunologist, a single additional dose of IVIG (400–600 mg/kg) may be given to restore intravascular IgG quickly for the purpose of infectious prophylaxis. A schedule for subsequent IVIG or SQIG infusions may then be developed in consultation with an immunologist. Importantly, we believe that the administration of additional IVIG doses to achieve a supra-physiologic serum IgG concentration has no role in the treatment of acute infections and should not be used in this manner in patients with primary immune deficiency [16 –18].

Bleeding

Intra-operative and post-operative hemostasis may be difficult in some primary immune deficiency disorders. Patients with Wiskott-Aldrich syndrome (WAS), in particular, pose a challenge from this perspective, as they are all microthrombocytopenic with one-third affected additionally by autoimmune vasculitis [19]. Aneurysm formation, especially of the aorta, is an important and often underappreciated feature of WAS that a surgical team should consider [20 –22]. In contrast to the platelet dysfunction in WAS, which is secondary to a cytoskeletal defect, patients with antibody deficiency diseases, including CVID and hyper-IgM syndromes, are susceptible to the development of autoimmune cytopenias that may affect platelets, erythrocytes, neutrophils, or various combinations thereof [23 –26]. The presence of pathologic autoantibodies in patients with an underlying defect in antibody production may seem paradoxical, but conforms to a fundamental theme in human immunobiology: The pathways important for immune protection also are essential for the maintenance of immune tolerance [6,27 –29].

An especially important consideration for surgeons is the presence of immune thrombocytopenia (ITP), as it may result in excessive bleeding. For the peri-operative management of ITP in patients with primary immune deficiency, we follow the general practice guidelines developed by the British Haematology Task Force [30]. The Task Force has established minimally acceptable pre-operative platelet counts that are stratified by anticipated surgical blood loss: >50,000/mcL for minor surgery, >80,000/mcL for major surgery. Patients with ITP who require surgery and have platelet counts below these thresholds may benefit from first-line immune modulatory therapy, including corticosteroids or high-dose IVIG (1–2 g/kg). The subsequent rise in platelet counts, although lasting only days to weeks, typically creates an adequate time frame for surgical intervention [30, 31]. For antibody-deficient patients with ITP, the use of corticosteroids or high-dose IVIG also is acceptable and appears equally effective in inducing a temporary rise in platelet counts. Many immunologists favor IVIG as a first-line therapy because of its additional immune protectant, rather than immunosuppressive, effects [25]. Also, for the immune-deficient patient already regularly receiving a replacement immunoglobulin product, there is a reduced risk of an adverse reaction to high-dose IVIG compared with most IVIG-naïve, immunocompetent ITP patients. Simultaneous use of IVIG and corticosteroids also is a common therapeutic choice and may provide a desirable combination of a relatively quick onset of action with a durable period of remission [32]. In some surgical situations such as trauma, ITP patients may experience a critical hemorrhage that requires more rapid hemostasis. In such instances, case reports suggest that strategies including simultaneous infusion of donor platelets in parallel with IVIG, or even administration of recombinant factor VIIa may serve important temporizing roles [31,33,34]. It is important to recognize that the latter of these strategies is not without thromboembolic risk [35]. More permanent interventions commonly used for patients chronically failing first-line therapies include splenectomy and B-cell depletion with rituximab. Although both strategies have been associated with iatrogenic infections, new evidence suggests that additional infectious risk in patients with primary immune deficiency can be mitigated with adequate immunoglobulin replacement therapy [24,36 –38]. We recommend consultation with a clinical immunologist when considering rituximab or splenectomy in a patient with primary immune deficiency who has an autoimmune cytopenia.

Gastrointestinal and Hepatic Complications

Primary immune deficiency disorders are associated with multiple gastrointestinal complications relevant to surgical care. Abscess formation in chronic granulomatous disease (CGD) results from insufficient superoxide production by phagocytes to destroy engulfed catalase-positive organisms [39,40]. Pathogens are instead quarantined in granulomatous structures that may act as mass-occupying lesions capable of occluding any hollow viscus. Obstructive symptoms will differ according to a granuloma's location. An intrahepatic granuloma may cause biliary obstruction requiring surgical drainage. In such patients, empiric antimicrobial therapy should be directed against Staphylococcus aureus, Pseudomonas aeruginosa, and Burkholderia cepacia until speciation information is available [41,42]. A granuloma located in the gastrointestinal tract may imitate some of the pathologic features of Crohn's disease [43,44]. Episodes of granuloma-related bowel obstruction are common in CGD patients but typically resolve quickly with corticosteroids [45,46]. Unfortunately, obstructive relapses are common [47]. Another common intestinal manifestation of primary antibody-deficiency diseases is chronic or episodic diarrhea [48]. Although many organisms have been reported, the classic pathogen isolated is Giardia lamblia, suggesting an important role for intestinal antibody-secreting cells in controlling this parasite [49]. Endoscopic examinations of the intestines of CVID patients reveal various abnormal features, including absent plasma cells, infiltrating intraepithelial lymphocytes, villous blunting, granulomas, nodular lymphoid hyperplasia, and lymphoma, all suggesting chronic inflammation secondary to infection or dysregulated mucosal immunity [50,51]. Given these histologic findings, it is not surprising that many CVID patients presenting with chronic diarrhea eventually are found to have inflammatory bowel disease [30]. It is our experience that in CVID cases complicated by enteropathy, antibiotic and immunosuppressive therapy must be applied thoughtfully.

Liver disease is also prevalent in patients with primary immune deficiency. A small proportion of this disease is iatrogenic, caused by hepatitis C virus infection acquired from contaminated IVIG preparations administered prior to 1991 [24, 52]. The most common non-infectious liver pathology in antibody-deficient patients is nodular regenerative hyperplasia, a feature generally thought to be autoimmune in nature [53]. Resultant cholestasis may cause portal hypertension, hepatic failure, or both [54,55]. Liver pathology in patients with T-cell immune deficiencies, including X-linked hyper-IgM syndrome and SCID, often is secondary to chronic infection with Cryptosporidium parvum, leading to sclerosing cholangitis [48,56,57]. Eradication of Cryptosporidium is difficult without immune reconstitution via hematopoietic stem-cell transplantation [58 –61].

Pulmonary Complications

Chronic lung disease, common in patients with primary immune deficiency and recurrent lower respiratory tract infections, is an important risk factor for the development of post-operative pulmonary complications [62,63]. In patients with antibody deficiency, immunoglobulin replacement therapy does decrease the frequency of pneumonia, although scarring from previous infections and chronic inflammation may result in irreversible lung damage [64,65]. Resultant are structural lung abnormalities, namely bronchiectasis, interstitial disease, emphysema, and, rarely, abscesses [66]. Bronchiectasis, once present, is a predictor of poor survival in CVID, as it provides a pulmonary environment suitable for P. aeruginosa, S. aureus, and Haemophilus spp. [67]. Patients with severe bronchiectasis may manifest pulmonary mechanics resembling those seen in patients with cystic fibrosis. Surgical interventions, including lobectomy and even lung transplantation, may be required in some cases [68,69].

A less well-understood pulmonary feature of some CVID patients is granulomatous inflammation, characterized by sarcoid-like lesions in lymph nodes [70]. Unlike the infected pulmonary granulomas found in CGD, infectious organisms are isolated infrequently from pulmonary granulomas in CVID patients [71]. For the above reasons, we recommend evaluating antibody-deficient patients and CGD patients with spirometry prior to surgical intervention requiring general anesthesia. Obstructive expiratory features, such as a forced expiratory volume in 1 sec (FEV₁) <70% of predicted or a FEV₁ as a percentage of forced vital capacity (FVC) <60%, should prompt high-resolution chest computed tomography to assess for pathology amenable to medical optimization prior to surgery [72].

Incision Healing

Selected primary immune deficiency diseases are associated with poor incision healing, an issue especially relevant to post-operative management. Patients with leukocyte adhesion deficiency (LAD) classically present with recurrent bacterial infections, cold abscesses, delayed umbilical cord separation, and poor incision healing [73]. Underlying this clinical presentation is a functional defect preventing neutrophil migration from the peripheral circulation into the tissues [74]. Patients with LAD often require aggressive surgical management post-operatively, including debridement and tissue grafting [73]. In contrast to patients with LAD, patients with CGD have an enhanced and persistent inflammatory response to bacteria that also may slow incision healing [75]. For this reason, surgeons caring for CGD patients have warned against early suture removal and advocated leaving surgical drains in place for a long period [76].

Special Considerations in Syndromic Immune Deficiency Diseases

Many primary immune deficiencies are caused by defects in molecules also vital to non-immunologic processes or organs. For instance, patients with autosomal dominant hyper-IgE syndrome resulting from mutations in STAT3 suffer chronic mucocutaneous candidiasis, as well as skeletal anomalies [77,78]. Recurrent pathological fractures, primarily of the long bones and ribs, occur in about 50% of patients [79,80]. These fractures may follow minor injury, and therefore, caution must be exercised when maneuvering patients in the operating room. Scoliosis of various degrees of severity is seen in more than 60% of these patients and warrants screening in order to guide necessary interventions [80]. Mucocutaneous candidiasis also has been reported in patients with gain-of-function STAT1 mutations associated with non-skeletal abnormalities, including dermatologic malignancies, fibromuscular dysplasia, and B-cell lymphopenia [81 –83]. Finally, a third genetic syndrome associated with mucocutaneous candidiasis, autoimmune polyendrocrinopathy candidiasis ectodermal dystrophy, is characterized by an array of autoimmune endocrine diseases, including type 1 diabetes mellitus, adrenal dysfunction, thyroid disease, hypoparathyroidism, and gonadal failure [84,85]. These are but three of many distinct syndromic immune deficiencies now described that have prominent non-immunologic features relevant to peri-operative care [86]. We include complex disease syndromes in this review to illustrate the importance, whenever possible, of pursuing a definitive diagnosis in patients with undefined primary immune deficiencies prior to surgical intervention. Once a specific diagnosis is made, an expectant plan of care can be developed with the aid of appropriate medical consultants to minimize surgical complications and optimize patient outcomes.

Author Disclosure Statement

No competing financial interests exist.

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