Autoimmune lymphoproliferative syndrome differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sharmi Biswas, M.B.B.S

Overview

Due to having overlapping presenting symptoms with other hematologic disorders, Autoimmune lymphoproliferative syndrome in children should be excluded from infection, autoimmune disease, inherited immune disorders, and lymphoma.

Differential Diagnosis

Differentiating diagnosis of Lymphoma	Symptoms					Signs			Diagnosis	Additional Findings
Differentiating diagnosis of Lymphoma	Fever	Rash	Diarrhea	Abdominal pain	Weight loss	Painful lymphadenopathy	Hepatosplenomegaly	Arthritis	Lab Findings	Additional Findings
Autoimmune lymphoproliferative syndrome	-/+	+	–	–	–	–	+	–	Increased CD4– and CD8– cells. Increased vitamin B 12.	Weakness, fatigue, pallor, bruise, mouth ulcers , slow wound healing, painless lymphadenopathy.^[1]
Lymphoma		–	–	+	+	–	+	–	Increase ESR, increased LDH	Night sweats, constant fatigue
Brucellosis	+	+	–	+	+	+	+	+	Relative lymphocytosis	Night sweats, often with a characteristic smell, likened to wet hay
Typhoid fever	+	+	–	+	–	–	+	+	Decreased hemoglobin	Incremental increase in temperature initially and than sustained fever as high as 40°C (104°F)
Malaria	+	–	+	+	–	–	+	+	Microcytosis, elevated LDH	“Tertian” fever: paroxysms occur every second day
Tuberculosis	+	+	–	+	+	+	–	+	Mild normocytic anemia, hyponatremia, and hypercalcemia	Night sweats, constant fatigue
Mumps	+	–	–	–	–	+	–	–	Relative lymphocytosis, serum amylaseelevated	Parotidswelling/tenderness
Rheumatoid arthritis	–	+	–	–	–	–	–	+	ESR and CRP elevated, positive rheumatoid factor	Morning stiffness
SLE	–	+	–	+	+	–	–	+	ESR and CRP elevated, positive ANA	Fatigue
HIV	–	–	–	+	+	+	–	+	Leukopenia	Constant fatigue

Disease	Differentiating signs and symptoms	Differentiating tests
Autoimmune lymphoproliferative syndrome	Most of the patients are in early childhood Generalized lymphadenopathy, splenomegaly	Elevated levels of CD4- and CD8-negative T lymphocytes, Genetic study showing mutation in apoptosis pathway of lymphocytes^[2]
CNS lymphoma	Patient is immunocompetent Focal symptoms indicative of a mass lesion Seizure	Single solitary ring enhancing lesion on CT or MRI
Disseminated tuberculosis	Prior history of residence in an endemic area Chronic cough, weight loss, hemoptysis	PCR of CSF for tuberculosis Mycobacterial culture of CSF Brain biopsy for acid-fast bacilli staining Culture and acid stain positive for acid-fast bacilli CXR shows cavitations
Aspergillosis	Pulmonary lesions in addition to CNS lesions Symptoms may include cough, chest pain, and hemoptysis	CSF fungal culture, galactomannan
Cryptococcosis	Symptoms include cough, chest pain, and hemoptysis	Cryptococcal antigen from CSF and serum CSF fungal culture
Chagas disease	History of residence in Central or South America Acute infection is rarely symptomatic Encephalitis or focal brain lesions Myocarditis Chronic infections in immunocompromised patients develop into encephalitis with necrotic brain lesions causing a mass effect	Trypanosoma cruzi in blood, tissue, or CSF, PCR of tissue or body fluids, and serologic tests
CMV infection	Most common CNS opportunistic infection in AIDS patients Presents with encephalitis, retinitis, progressive myelitis, or polyradiculitis In disseminated disease, it involves both the liver and kidneys	Brain CT/MRI/biopsy: location of lesions is usually near the brain stem or periventricular areas PCR of CSF with detectable virus is diagnostic Brain biopsy with + staining for CMV or evidence of owl’s eyes is also diagnostic, but it is rarely performed because of the location of brain lesions
HSV infection	Seizures, headache, confusion and/or urinary retention can be seen in disseminated disease, which usually affects only the immunocompromised or acute infections In pregnant women, it may be associated with concurrent genital/oral lesions; can be spread to the neonate during acute infection in the mother, or via viral shedding in the birth canal Neonatal HSV can range from localized skin infections to encephalitis, pneumonitis, and disseminated disease	Brain CT/MRI/biopsy: location of lesions is usually the medial temporal lobe or the orbital surface of the frontal lobe. PCR of CSF with detectable virus is diagnostic
Varicella Zoster infection	Multifocal involvement has subacute course, usually only in immunosuppressed, with headache, fever, focal deficits, and seizures. Unifocal involvement is more typically seen in immunocompetent hosts, occurring after contralateral cranial nerve herpes zoster, with mental status changes, TIAs, and stroke Disseminated varicella zoster virus can occur in adults during primary infection, presenting with pneumonitis and/or hepatitis Disease is a vasculopathy with hemorrhage and stroke	PCR of CSF with detectable virus is diagnostic
Brain abscess	Associated with sinusitis (abutting the sinuses) or with bacteremia Signs and symptoms includes fever and necrotizing brain lesions with mass effect	CSF culture or culture of brain abscess
Progressive multifocal leukoencephalopathy	Symptoms are often more insidious in onset and progress over months. Symptoms include progressive weakness, poor coordination, with gradual slowing of mental function. Only seen in the immunosuppressed. Rarely associated with fever or other systemic symptoms	PCR of CSF for JC virus Biopsy reveals white matter lesions and not well-circumscribed lesions.

References

↑ Shah, Shaili; Wu, Eveline; Rao, V. Koneti; Tarrant, Teresa K. (2014). “Autoimmune Lymphoproliferative Syndrome: an Update and Review of the Literature”. Current Allergy and Asthma Reports. 14 (9). doi:10.1007/s11882-014-0462-4. ISSN 1529-7322.
↑ Lambotte, O.; Neven, B.; Galicier, L.; Magerus-Chatinet, A.; Schleinitz, N.; Hermine, O.; Meyts, I.; Picard, C.; Godeau, B.; Fischer, A.; Rieux-Laucat, F. (2012). “Diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency in adults”. Haematologica. 98 (3): 389–392. doi:10.3324/haematol.2012.067488. ISSN 0390-6078.

[ShahWu2014-1] Shah, Shaili; Wu, Eveline; Rao, V. Koneti; Tarrant, Teresa K. (2014). “Autoimmune Lymphoproliferative Syndrome: an Update and Review of the Literature”. Current Allergy and Asthma Reports. 14 (9). doi:10.1007/s11882-014-0462-4. ISSN 1529-7322.

[LambotteNeven2012-2] Lambotte, O.; Neven, B.; Galicier, L.; Magerus-Chatinet, A.; Schleinitz, N.; Hermine, O.; Meyts, I.; Picard, C.; Godeau, B.; Fischer, A.; Rieux-Laucat, F. (2012). “Diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency in adults”. Haematologica. 98 (3): 389–392. doi:10.3324/haematol.2012.067488. ISSN 0390-6078.

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