|Year : 2020 | Volume
| Issue : 1 | Page : 18-23
Insight into the challenges in diagnosis and management of infections in adults with primary immunodeficiency diseases: A study from AIIMS, New Delhi
Bharath Gangadharaiah1, Monalisa Sahu2, Arvind Kumar1, Piyush Ranjan1, Prayas Sethi1, Naveet Wig1
1 Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
2 Department of Medicine and Microbiology, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||04-Dec-2020|
|Date of Decision||10-Dec-2020|
|Date of Acceptance||14-Dec-2020|
|Date of Web Publication||31-Dec-2020|
Dr. Arvind Kumar
Department of Medicine, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Primary immunodeficiency diseases (PIDDs) comprise a group of genetic disorders which are characterized by abnormalities involving one or more components of the immune system. Most of them are diagnosed in children and adolescents. Advancement in medical management has resulted in most of these patients living till adulthood. Moreover, few PIDD patients are diagnosed for the first time in their adulthood. In most of the developing countries, where the prevalence of infectious disease is quite high, diagnosis of patients presenting in adulthood with PIDDs poses a major challenge. The diagnosis may be delayed or even missed altogether when they present late in adulthood. Hence, having in-depth knowledge regarding common PIDDs seen in this age group, the natural course of these diseases and the wide range of clinical spectrum with which these patients can present is quite imperative for a physician dealing with such patients. This case series provides the details of three such PIDD patients presenting in the late adolescence and adult age group, along with a comprehensive review on the common and uncommon infections occurring among PIDD patients in this age group.
Keywords: Adulthood, infection, management, primary immunodeficiency
|How to cite this article:|
Gangadharaiah B, Sahu M, Kumar A, Ranjan P, Sethi P, Wig N. Insight into the challenges in diagnosis and management of infections in adults with primary immunodeficiency diseases: A study from AIIMS, New Delhi. J Prim Care Spec 2020;1:18-23
|How to cite this URL:|
Gangadharaiah B, Sahu M, Kumar A, Ranjan P, Sethi P, Wig N. Insight into the challenges in diagnosis and management of infections in adults with primary immunodeficiency diseases: A study from AIIMS, New Delhi. J Prim Care Spec [serial online] 2020 [cited 2021 Mar 4];1:18-23. Available from: http://www.jpcs.com/text.asp?2020/1/1/18/305882
| Introduction|| |
Primary immunodeficiency diseases (PIDDs) comprise a group of genetic disorders characterized by abnormalities involving one or more components of the immune system. Several genetically defined single-gene inborn errors of immunity, amounting to over 300, have now been identified as a cause of PIDD. Although the nationwide data on the prevalence of PIDDs in India is lacking, statistical projections have been done, which estimate the number of patients with PIDD likely to be more than one million. Abnormalities in humoral immunity contribute to more than 50% of the cases. Susceptibility to bacterial infections is a major manifestation in this subset of patients with PIDD. Anomalies in the T-cell compartment account for a fewer primary immune deficiencies but are considerably more severe and often have grave outcomes.
In most of the developing countries, where the prevalence of infectious disease is quite high, diagnosis of the patients presenting in adulthood with PIDDs poses a major challenge. The diagnosis may be delayed or even missed altogether when they present late in adulthood. Adults presenting with PIDD can manifest with well-defined syndromes, as well as subtle and often subclinical immune defects. These clinical conditions are expressed with variable penetrance and, on several occasions, go unrecognized in general clinical practice. Mostly, these individuals are recognized to be immunodeficient after undergoing extensive investigations for some other unforeseen, unusual, recurrent, or severe infections.
A retrospective analysis was conducted by Srinivasa et al. on the clinical phenotypes of adult PIDDs referred to the Immune Deficiency Treatment Centre, dedicated to the diagnosis and care of adults with primary immune deficiencies in Montreal, Canada. Over the 10-year study period, 244 patients were diagnosed to have immune deficiency. No major difference was observed in the median age based on gender. The median age was 48 years in men and 45 years in women. Of the 244 patients diagnosed with immune deficiency, 210 had primary immune deficiency, whereas the remaining 34 had a secondary immune deficiency. Among the 210 patients with primary immune deficiency, 167 had the European Society for Immunodeficiencies/Pan-American Group for Immune Deficiency defined primary immune deficiency, whereas 43 had a novel or undefined deficiency. Common variable immune deficiency was the most common primary immune deficiency observed contributing to 72/167 (43%) in the study. Immunoglobulin A (IgA) deficiency, though detected more commonly than common variable immune deficiency, was underrepresented in this study, being detected in 25/167 (15%) of the cases. Hypogammaglobulinemia with infections that did not meet the diagnostic criteria for common variable immune deficiency was detected in 17/167 (10%), and idiopathic CD4 T-lymphopenia was detected in 12/167 (8%) of the cases.
| Methods|| |
All these patients who were managed as inpatients in the Department of Medicine at our institute between January 2018 and December 2019 were reviewed. Few cases, which were interesting, thought provoking, took lot of literature search and discussions among the peers were selected. Informed consent was taken from patients or family members.
A 41-year-old male presented to our hospital with complaints of small bowel-type diarrhea since 8 months. He was a diagnosed case of common variable immunodeficiency (CVID) since 18 years of his age. He had a history of recurrent sinus and pulmonary infections when the diagnosis was made. He was receiving intravenous immunoglobulin (IVIG) every 45 days for about 8 years after diagnosis. Eight years back, he developed gastrointestinal symptoms. He was then diagnosed to have giardiasis, and his symptoms resolved with treatment. However, he had a history of recurrent giardiasis since then. The frequency of IVIG administration was increased to every 30 days. Two years back, he was diagnosed to have cutaneous TB after histopathological examination of his skin lesions which showed granulomas and AFB-positive bacilli. He received 6 months of ATT, following which the granulomas had resolved. Eight months back, he again started having diarrhea. Stool examination revealed Giardia cysts. However, this time, the symptoms were unresponsive to treatment. He underwent extensive workup from a private hospital. Positron emission tomography/computed tomography (CT) done as part of evaluation showed a lesion with high uptake in the thyroid gland. Fine-needle aspiration cytology from the thyroid gland showed atypical cells suggestive of malignancy. Thyroidectomy was then performed, which after histopathological examination revealed follicular carcinoma. There was no evidence of local spread, spread to lymph nodes, or distant metastasis. His chronic diarrhea did not resolve, and he was referred to our hospital for further management. His duodenal biopsy was done, which showed Giardia trophozoites. He was given high-dose metronidazole for 3 weeks, but there was no improvement in his symptoms. The patient developed a hospital-acquired infection with LRTI. Even though managed aggressively with broad-spectrum intravenous (IV) antibiotics and supportive care, he expired due to severe sepsis with MODS.
A 16-year-old boy was admitted to our hospital with complaints of high-grade continuous fever, abdominal pain and distension, bilateral lower-limb swelling, jaundice, and dyspnea for 10 days. On admission, the patient was conscious and oriented. He was tachypneic, with a respiratory rate of 34/min, temperature of 102°F, blood pressure of 94/59 mmHg, and arterial oxygen saturation of 84% on ambient air. He was icteric, and bilateral lower-limb pitting edema was present. Abdominal examination had significant findings of tenderness in the right hypochondrium, liver was palpable 5 cm below the right costal margin, and ascites was present. Air entry was reduced in the right mammary, infra-axillary, and infrascapular area. The rest of the examination was unremarkable.
Initial blood investigations showed raised TLC and bilirubin, along with anemia, thrombocytopenia, and coagulopathy. Chest radiograph revealed right lower zone consolidation and pleural effusion. Contrast-enhanced CT (CECT) of the abdomen showed multiple hypodense lesions in the liver and spleen with ascites, mural thickening involving the ascending colon with superior mesenteric vein thrombosis, along with periportal and peripancreatic nodal enlargement. Ascitic fluid GeneXpert for Mycobacterium tuberculosis was positive. His urine Histoplasma antigen was positive. However, no other classical signs of Histoplasma infection could be appreciated. His blood culture was repeated multiple times which turned to be sterile on all occasions. The culture of pus aspirated from his liver lesions was negative for any sort of growth even after prolonged incubation, and the MGIT culture for M. tuberculosis was also negative. The patient was diagnosed to have pyogenic liver abscess in association with M. tuberculosis and indolent Histoplasma infection. Human immunodeficiency virus (HIV) serology of the patient was negative. In view of his fulminant presentation at a young age, we considered primary immunodeficiency workup. He had a low neutrophilic oxidative index, and his dihydrorhodamine test (DHR test) was positive, suggestive of chronic granulomatous disease (CGD).
The patient was initially treated with broad-spectrum IV antibiotics, ATT, and antifungals. Percutaneous drainage of the liver abscesses was done. His clinical condition improved, and he was discharged on lifelong trimethoprim-sulfamethoxazole and itraconazole prophylaxis. He is currently doing well and is under 6 monthly follow-up visits.
A 17-year-old student had a history of repeated hospital visit since childhood for complaints of dry cough, shortness of breath on exertion, and low-grade fever. He was diagnosed as a case of pulmonary tuberculosis before and received ATT at is 14 years of age. There was no improvement in his complaints. He presented to our institute with the above complaints. He also had a history of repeated appearance of pustular lesions all over the body.
On examination, he had furuncles, bilateral clubbing, and low BMI. Chest examination revealed bilateral crepitations in the infrascapular area. CECT chest showed extensive bronchiectasis in bilateral upper lobes and left lower and middle zone along with bulla in bilateral lung, fibrotic lesions, and mild pleural thickening.
Pus aspirated from the furuncles on bacterial culture grew Staphylococcus aureus. Sweat chloride test was done, which was negative. Cystic fibrosis F508 mutation analysis was done and was negative. Serum IgG Aspergillus test was positive. Serum alpha 1 antitrypsin was negative.
There was a history of similar complaints in his elder sister. With the suspicion of PIDD, immunological workup was done and it revealed reduced nitric oxide index, and his DHR test was positive, suggestive of CGD. His furuncles resolved with appropriate treatment. Currently, he is on itraconazole and trimethoprim-sulfamethoxazole prophylaxis. He is doing well on follow-up.
A 27-year-old female presented with complaints of swelling and redness of the right eye along with holocranial dull aching headache. She revealed that she had a furuncle over the right side of the face 1 day before the presentation. The next day, she developed sudden-onset left-sided hemiparesis. The patient arrived at our hospital after 7 days of illness. There was no history of fever, vomiting, and no blurring of vision, no diplopia. On examination, her right eyelid was swollen and red with raised local temperature along with minimal conjunctival suffusion and redness. There was no pus discharge from the eye. Right LMN facial nerve and left-sided hypoglossal nerve palsy was present. Pronator drift test was present on the left side, along with slight decline in sensory perception of the left half of the body. UMN signs on the left side were present. All cerebellar signs were positive, including gross gait ataxia, finger-to-nose, and heel-to-shin tests. She had gaze-evoked nystagmus with full eye fields. Meningeal signs were absent. The rest of the systemic examination was normal.
Initial blood investigations revealed hyperleukocytosis with predominant neutrophilia, lymphocytopenia, and thrombocytopenia. Her serum globulin levels were low. Results of renal and liver function tests, electrolytes, and lactic acid were all normal. Urinalysis revealed the absence of pus cells, protein, or glucose. Chest radiography revealed small pleural-based rounded opacity in the right hemithorax. CECT of the head and paranasal sinuses revealed right orbital cellulitis and mucosal thickening in few of the right anterior ethmoidal air cells; the rest of the paranasal sinuses are normal. Both superior ophthalmic veins were dilated. She was empirically started on co-amoxiclav and linezolid for cellulitis. Magnetic resonance imaging head and orbit was performed, which showed T2 hyper/T1 hypointensity in the prepontine cistern on the right anterior aspect of the pons, extending into the right internal acoustic meatus along with localized contrast enhancement along meninges in this region and in bilateral occipital horns. T2/FLAIR hyperintense foci were also seen in the pons and right cerebellar peduncle, showing diffusion restriction suggestive of infarct. Cerebrospinal fluid (CSF) evaluation showed that normal CSF opening pressure was 5 cm of water, with cytological and chemical features of acute bacterial meningitis (TLC: 100/mm3 with 80% polymorphonuclear cells, red blood cells: 60/mm3, and glucose: 30 mg/dL with RBS 109 mg/dL). Cryptococcal antigen test, GeneXpert, ADA, HSV PCR, and CMV PCR were negative, and the bacterial culture was sterile. Her antibiotics were escalated to IV meropenem and vancomycin. Further evaluation was done for possible origin of the orbital cellulitis and meningitis as there was only minor thickening of mucosa of anterior ethmoid cells and no other adjacent source for meningitis. A CECT chest and abdomen revealed empyema with thickened parietal and visceral pleura, multiple septic infarcts in the lungs (bilateral, more on the right), and bulky kidneys with 2 wedge-shaped infarct on the right and 1 on the left suggestive of pyelonephritis. Two-dimensional echocardiography revealed no vegetations. Blood culture grew Klebsiella pneumoniae sensitive to imipenem and colistin. Ultrasonography-guided aspiration of the empyema was done which did not yield growth on culture for bacterial and fungal organisms, and GeneXpert was negative. We evaluated the cause of her lack of febrile response to disseminated infection and ruled out HIV, diabetes, nephrotic syndrome, and other acquired causes.
Flow cytometry revealed suppressed levels of T- and B-cells. She had a significant improvement in strength, sensory symptoms, and coordination of the left body and a decrease in size of right eye swelling but no difference in right facial palsy. She was advised gait training and facial physiotherapy and discharged on oral antibiotics. Repeat immunodeficiency workup revealed normalization of lymphocyte counts and serum globulin levels.
| Discussion|| |
PIDDs are relatively uncommon among adults, with the exception of IgA deficiency. Lack of a single clinical phenotype, accompanied by low index of suspicion, poses a significant challenge in the diagnosis of these patients in general clinical practice. In accordance with the wide spectrum of possible inherent defects, there is a diverse clinical phenotype of the immune deficiency diseases. Clinical presentation is mainly due to the severity and frequency of the resultant infections or autoimmune process.
The initial workup of the patients with suspected PIDD should be directed to a particular arm of the immune system, guided by the causative microbial agent. For example, individuals with impairment of the humoral immunity arm are more likely to develop bacterial infections, while individuals with T-cell defects are more likely to develop severe viral and fungal infections. Most of the adult primary immune deficiencies detected in the clinical practice depict humoral immune defects, which are generally less fatal in the short term. The functioning of the T-cell arm of the immune system compensates for it, thus offering partial protection in these individuals. On the contrary, T-cell defects and combined immune deficiencies are seldom seen in adults as they usually have a more severe, often fatal childhood clinical phenotype.
A previously healthy individual if presents with chronic or recurrent infections, it should prompt further evaluation for eliminating all possible predisposing factors. Ruling out secondary causes of immunodeficiency is imperative in the workup of the patients with recurrent infections to ascertain the exact cause of the manifestations. After ruling out the secondary causes, investigations should be further directed to detect the presence of PIDDs.
Although there have been an increasing number of individuals who are diagnosed with primary immune defects, still, secondary etiologies continue to be the leading cause of immunodeficiency in adults. Infectious diseases including HIV, CMV, and EBV and malignancy including B-cell malignancies, chronic lymphocytic leukemia, and non-Hodgkin lymphoma have been well described to be associated with secondary hypogammaglobulinemia.
Exposure to medications can also be responsible for secondary immune deficiency, glucocorticoids being the most common offending agents. Other medications, including biologics, antimalarials, captopril, gold salts, and antiepileptics including carbamazepine and phenytoin, have also been implicated. Finally, systemic disorders resulting in either hypercatabolism or accelerated loss of immunoglobulins, for instance, as in protein-losing enteropathy, essentially needs to be ruled out.
Common variable immunodeficiency
The most frequently diagnosed form of adult primary immune deficiency is CVID. It is characterized by hypogammaglobulinemia, along with a spectrum of heterogeneous clinical manifestations, including recurrent respiratory tract infections, and other complications such as autoimmune and lymphoproliferative disorders. In a study conducted by Nepesov et al. among the 44 patients with CVID in a tertiary care center in Turkey over a period of 22 years, 28/44 (63.6%) manifested with sinopulmonary infection as the first presentation of the disease. It included pneumonia in 23/44 (52.2%), otitis media detected in 4 patients (9.1%), and sinusitis in 1 patient (2.3%). Fever of unknown origin was detected in five patients. Twelve patients were diagnosed after 10 years of age. A comparatively lower rate of sinopulmonary infection (41.7% vs. 71.9%) was detected in the older patients as the first manifestation of the disease, whereas a higher rate of bronchiectasis (75% vs. 43.7%) was observed. Streptococcus species and Haemophilus influenzae serotype B (HiB) contributed the most in these sinopulmonary infections. M tuberculosis was detected in a 21-year-old girl with bronchiectasis, with severe absence of CD4+ T-cells (<600 cells/mm3). M. tuberculosis infection can also be an initial presentation. There are case reports on MTB infection diagnosed in adults with CVID. However, as MTB is endemic in India, so clinicians have a low index of suspicion for CVID in patients with MTB infection.
Although the failure of B-cell differentiation is the major mechanism involved in CVID, leading to reduced secretion of immunoglobulins resulting in severe bacterial infections, the disease has often been associated with defects in T-cell function. Viral infections are caused by enteroviruses, which include poliovirus, coxsackievirus, and echovirus. In a study conducted by Sperlich et al., respiratory viruses including rhinovirus, adenovirus, RSV, human metapneumovirus, influenza, and parainfluenza virus were detected in 56% of the exacerbations. Norovirus was detected to be the most common cause of viral gastroenteritis in the patients with CVID, and is also associated with periods of prolonged shedding in both symptomatic and asymptomatic individuals. Viruses belonging to the Herpesviridae family including CMV and EBV have been involved in diseases ranging from infectious mononucleosis (IM), retinitis, enteritis to pneumonitis in the patients with CVID.
Due to advancement in medical field, patients with CVID are living for more than 2 decades after their diagnosis. These patients need close clinical follow-up and continuous antimicrobial prophylaxis unless they undergo stem cell transplantation. They are prone to develop more complicated and severe infections.
Chronic granulomatous disease
CGD is an inherited disorder of primary immunodeficiency, characterized by functional impairment of the NADPH oxidase complex in neutrophils and monocytes. It usually manifests with recurrent and severe infections, and is associated with dysregulated inflammation and autoimmunity. Catalase-positive microorganisms comprise the major subset of organisms causing infection in the CGD patients, the most common sites of infection being lungs, skin, lymph nodes, and liver. Aspergillus species, S. aureus, Burkholderia cepacia, Serratia marcescens, Nocardia species, and Salmonella species are the organisms commonly implicated for causing infections in the patients with CGD. In developing countries, Bacille Calmette–Guerin and M. tuberculosis have been identified as important pathogens in the CGD patients. Patients with CGD may present at any age starting from infancy to adulthood, although the majority of the patients are diagnosed at <5 years of age. Clinical presentations include granuloma and abscess formation in multiple sites, including skin, liver, lungs, and lymph nodes manifesting as cellulitis or abscesses, liver abscess, pneumonia, and lymphadenitis, respectively. Multiple diffuse vesiculopustular lesions, osteomyelitis, and splenic lesions due to these organisms have also been reported.
Multiple infections causing severe clinical conditions can be the initial presentation in CGD patients. Our second case was a 16-year-old adolescent who presented in critical condition due to polymicrobial infection and multiple liver abscesses. Sometimes, diagnosis of CGD requires a high index of suspicion when it presents at a later age. Our third case of the series is such an example.
Immunoglobulin A deficiency
IgA deficiency is the most common primary immunodeficiency detected in adults. It is characterized by diminished serum levels of IgA along with a concomitant lack of secretory IgA. Normal levels of other immunoglobulin isotypes are detected. Individuals older than 4 years with blood levels of IgA below 7 mg/dl but having normal levels of IgG and IgM are diagnosed to have IgA deficiency. A normal antibody response to vaccines is noticed in these patients. Moreover, IgA deficiency needs to be excluded during the workup for other causes of hypogammaglobulinemia and defects in T-lymphocytes.
Primary IgA deficiency is considered to be a permanent disorder. Secondary causes may be associated with infection or medications, but these cases are reversible.
Most of the individuals with this disease are asymptomatic (85%–90%) and are identified coincidentally. Individuals with IgA deficiency may be recognized among blood bank donors in the absence of any clinical findings. However, recurrent infections of the respiratory and the gastrointestinal tract may be detected along with certain allergic and autoimmune manifestations and malignancies in some of the individuals. A small percentage of patient progress to develop CVID.
Recurrent sinopulmonary infections comprise the most common manifestations seen in these individuals, caused mostly due to bacteria, including H. influenzae and Streptococcus pneumoniae. End-organ damage such as bronchiectasis may develop secondary to recurring or chronic infections in some of the patients. A higher risk of developing severe infections and complications is seen in patients with associated antibody deficiency such as IgG2 subclass deficiency. Giardiasis is the most common gastrointestinal infection seen in individuals with IgA deficiency. Impairment of the protective barrier of the gastrointestinal system in IgA deficiency promotes the protozoa such as Giardia lamblia to adhere to the epithelium, leading to proliferation, and infection. Structural damage to the intestinal villi may subsequently cause malabsorption.
Infections causing secondary immunodeficiency
Indirect effects on the immune system have been observed with infections by viruses and intracellular bacteria, consequently leading to the induction of immunosuppression. It has been suggested to be caused by pathogens selectively infecting lymphocytes, for example, T-cells being infected with HIV Types I and II or with human T-cell lymphotropic virus Types I and II. On the other hand, human B-lymphocytes are more prone to infection by Epstein–Barr virus (EBV). Herpes simplex and measles virus can infect both B- and T-lymphocytes leading to severe immunosuppression. Hence, lymphocyte depletion could be the predominant cause of immunosuppression, attributable to the viral infection. Resulting immunosuppression thus leads to increased susceptibility to opportunistic infections in these infected hosts.
The host–parasite cellular interaction plays a crucial role in determining the underlying mechanisms of immunosuppression due to the bacterial infection, and the outcome is elicited by the host immune mediators released causing a shift in the balance between Th1 and Th2 responses. Prevention of phagolysosome biogenesis, inhibition of mechanisms of cellular autophagy, and inhibition of antigen presentation., The several microbial virulence factors released finally culminate in induced immunosuppression, leading to the establishment of a disease process at their predilection sites. Furthermore, a rich environment is offered with prolonged immunosuppression for the microbial growth, replication, and pathogenicity conduction. Consequently, the resulting disease process becomes much exacerbated due to microbial abundance and invasiveness, which occurs secondary to shift in balance between pro-inflammatory and anti-inflammatory factors of the host. Patients with severe and multiple infections without any evident predisposing factors are often seen in clinical practice. Therefore, all these patients should be extensively worked up for secondary causes before investigating for PIDDs. Our last case in this series presented severe CNS infection. On initial evaluation, she had reduced lymphocyte counts, along with hypoglobulinemia. However, subsequently, when the patient recovered from illness, her lymphocyte counts and globulin levels in serum are normalized.
Viral infections in adult primary immunodeficiency diseases
Immunodeficiency disorders primarily affecting the cytokine production and T-cell differentiation predispose to the development of viral infections. It can be exemplified by X-linked lymphoproliferative syndrome Type 1 (XLP1), which is associated with aberrant T- and NK-cell cytokine production and has a strong association with EBV infection. It thus results in severe IM, hemophagocytic lymphohistiocytosis (HLH), and also increased occurrence of EBV-associated B-cell lymphomas. Most of the patients with X-linked lymphoproliferative syndrome Type 1 are diagnosed at ages younger than 10 years, and there are only a few adult patients.
EBV infection and associated immunodeficiency disease necessitate special mention. Early identification of any possible primary immunodeficiency or a chronic active EBV infection and HLH, is essential in patients presenting with severe EBV infections. Tests providing useful insight into the identification of the suggestive clinical conditions with inability to control EBV infections include immunological phenotyping of NK-, T-, and B-cell differentiation. Functional assays including cytotoxic cell-killing function and cytotoxic granule release also provide a clue to the diagnosis. Isolation and amplification of genomic DNA from peripheral blood mononuclear cells have been used to screen for possible immunodeficiency.
A symptomless or mild infection is the usual presentation of primary infection with EBV, which typically occurs in childhood. Primary EBV infection, if occurs in adolescence or adulthood, results in a 25%–70% higher risk of developing a symptomatic EBV infection, termed as IM. Despite the majority of the individuals infected with EBV usually having an asymptomatic or self-limiting clinical course, there is a broad spectrum of pathological responses to infection in these individuals, which encompasses prolonged fever and lymphoproliferation (severe IM), HLH, autoimmunity, and malignancy. Unregulated cytotoxic and inflammatory responses to EBV-infected B-cells, diminished T-cell or NK-cell immune surveillance of the EBV-infected cells, or EBV infection in non-B cells are the suggested pathways leading to the manifestations in these patients.
HLH is defined as a severe, life-threatening immunodysregulatory disorder which results from the uncontrolled activation and proliferation of T-cells and macrophages, causing excessive production of cytokines, hyperinflammation, and tissue damage. It has been classified as either primary HLH, when there is a family history of the disorder or an identified genetic defect is detected, or as secondary HLH, when associated with infection, rheumatological disorders or malignancy. Furthermore, HLH is also being recognized as a complication of the more “classical” primary immunodeficiencies (PIDDs). EBV is a significant infectious trigger for both primary and secondary HLH. X-linked lymphoproliferative disease and X-linked inhibition of apoptosis are the two common PIDD disorders associated with HLH and uncontrolled EBV infection. CVID, SCID, and CGD patients have also been detected to be associated with EBV infections.
| Summary|| |
PIDD is commonly diagnosed in children. Uncommonly, they are first diagnosed in late adolescence and adults. Due to the high prevalence of infectious disease in developing countries, the treating physician carries low suspicion for PIDD in these populations even when they present with severe or recurrent infection and infection with atypical pathogens. Further, adults can present with well-defined syndromes, as well as subtle and often subclinical immune defects. Inquisitive thinking and comprehensive evaluation to rule out secondary causes of immunodeficiency and workup for PIDD will lead to long-term better management of patients.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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