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Without guile: a case of drug-induced aseptic meningitis in a patient with idiopathic CD4 lymphocytopenia LT Benjamin S. Vipler, MD, Associate, Walter Reed National Military Medical Center, Bethesda, MD. CPT Jason J. Nam, MD, Associate, Madigan Army Medical Center, Tacoma, WA. LCDR Andrew G. Letizia, MD, Walter Reed National Military Medical Center, Bethesda, MD. Christina M. Schofield, MD, FACP, Madigan Army Medical Center, Tacoma, WA. MAJ David M. Callender, MD, FACP, Walter Reed National Military Medical Center, Bethesda, MD. Disclosures • The views expressed in this case are those of the author and do not necessarily reflect the official policy or position of the Departments of the Army, Navy, Defense, nor the US Government. • I have no financial disclosures. Chief Complaint • Shaking • Fever • Neck pain History of Present Illness • 62 year old African-American man – Idiopathic CD4+ lymphocytopenia (ICL) – Diabetes mellitus type II – Psoriatic arthritis • • • • Fever, rigors, then headache, posterior neck pain/stiffness Acute onset, 12 hours prior to being seen in ER “I never get headaches” Exacerbation of chronic polyathralgias History of Present Illness Continued • Started on trimethoprim/sulfamethoxazole (TMP/SMX) for pneumocystis prophylaxis – Last CD4+ count 120 (cells/µl) one month earlier – First pill of TMP/SMX was that morning • Dose administered 3 hours prior to symptoms What is Idiopathic CD4+ Lympho(cyto)penia • Defined by CDC in 1992 (also called “severe unexplained HIV-seronegative immune suppression” by WHO) – Decreased CD4 T lymphocytes • <300 cells/µl OR • <20% of total T cells – 2 separate lab draws ≥6 weeks apart – No evidence of HIV-1 or HIV-2 – Absence of defined immunodeficiency or T cell lowering therapy • Not sexually transmitted • No gender predilection • No clear age of onset Walker et al. Curr Opin Rheumatol 18 (4): 389–95. What is Idiopathic CD4+ Lympho(cyto)penia • Some evidence on BM biopsy of decreased T cell precursors – Similarities seen in CVID patients with low CD4 cell counts • Asymptomatic to severely ill • Similar illnesses as HIV infected patients • Treatment focused on prophylaxis – – – – No guidelines for ICL Extrapolated from HIV Pneumocystis More frequent cervical cancer screening Walker et al. Curr Opin Rheumatol 18 (4): 389–95. Past Medical History • ICL – Diagnosed 2002 – Multiple bone marrow biopsies unrevealing • Chronic recurrent fevers without underlying infectious etiologies – Not associated with headache or neck pain • Recurrent pneumonia • Moderate to severe plaque psoriasis – Psoriatic arthritis • Multiple unprovoked pulmonary emboli – Lifelong anticoagulation Past Medical History Continued • • • • • • • Morbid obesity Diabetes mellitus type II Hypertension Hyperlipidemia GERD Left elbow surgery after trauma Excisional lymph node biopsy Past Medical History Continued • Similar episode of current presentation “years ago” – – – – – – Same symptoms Body habitus prohibited acquisition of spinal fluid Treated empirically for meningitis Required ICU admission for “coma” per wife Recovered Circumstances surrounding this episode unknown Medications • • • • • • • Loratidine 10mg Lisinopril 40mg Glipizide XL 10mg Triamterene/HCTZ 37.5/25mg Nifedipine 30mg Atorvastatin 40mg Esomeprazole 40mg • • • • • • • Vitamin B12 Vitamin C Insulin Metformin XR 500mg twice daily Acetaminophen with codeine Morphine Fentanyl (transdermal) 125mcg/hr Vital Signs • • • • • • • BMI 47 Temp: 39.1° C (102.4° F) HR 93, regular BP 115/48 RR 20 SpO2 98%, room air Pain score 7/10 Physical Examination • Awake, alert, oriented. Well developed. No acute distress – Occasional shivers. No rigors observed • • • • • Mucosa moist. Oropharynx without erythema/exudates No nystagmus. Mild conjunctivitis Neck flexion to 60 degrees, then limited by pain in the poster neck Posterior neck slightly tender. No significant lymphadenopathy Normal respiratory depth, rhythm and effort – Slightly increased rate to low 20s • Lungs clear to auscultation without wheezes/rhonchi/crackles. Physical Examination continued • • • • • Regular rate and rhythm II/VI early systolic murmur at left upper sternal border Soft, nontender, nondistended, without peritoneal signs Normoactive bowel sounds. No bruits Extremities with limited joint mobility. – No increased warmth in any particular joint. • Scattered hyperpigmented plaques – Consistent with known psoriasis • Cranial nerves II-XII intact. • Brudzinski sign negative. Kernig sign difficult to perform with arthropathy Labs – – – – – – AST 18 ALT 18 Alk phos 111 Total bili 0.3 Total protein 7.4 Albumin 3.9 – Lipase 30 – INR 1.5 – Anion gap 13 – Lactate 2.4 – UA negative – Cardiac enzymes negative Imaging / Diagnostics Initial Assessment/Plan • Sepsis with potential CNS source – IV fluid resuscitation – Empiric meningitis coverage for an immunocompromised host • • • • Ampicillin Ceftriaxone Vancomycin Acyclovir – TMP/SMX held Hospital Course • • • • • • High fevers continued despite broad spectrum antimicrobials Blood and urine cultures no growth to date Influenza PCR negative Cryptococcus serum antigen negative Body habitus prevented lumbar puncture until hospital day (HD) 3 Head CT obtained prior to LP – Negative Spinal Fluid Analysis • Tube #3 – Color/appearance: pink, hazy – WBC: 219 cells per mm3 • PMN: 90% • Lymph: 2% • Mono: 8% – RBC: 5040 cells per mm3 • Peripheral blood contamination • WBC corrects to 207 cells per mm3 – Glucose: 50 mg/dL – Protein: 56 mg/dL Spinal Fluid Analysis Continued • • • • • • • • Gram stain: no organisms Arbovirus panel negative Cytomegalovirus negative Varicella zoster negative Cryptococcus negative Enterovirus negative Herpes simplex 1&2 negative Bacterial and fungal cultures negative Hospital Course • • • • • High fevers continued On HD 4, patient found altered with global aphasia Transferred to intensive care unit Intubated for airway protection Neuroimaging with CT and MRI did not reveal cause Hospital Course • • • • Condition improved with supportive care Extubated the following day Last fever noted just prior to ICU transfer Antimicrobials weaned – Acyclovir discontinued HD 5 – Ampicillin, vancomycin discontinued HD 6 – Ceftriaxone discontinued HD 10 Hospital Course • • • • On HD 7, started on dapsone for pneumocystis prophylaxis Developed a fever to 38.4° C (101.2° F) Dapsone abruptly discontinued Did not have fever recurrence for the duration of hospitalization Hospital Course • • • • • On HD 7, started on dapsone for pneumocystis prophylaxis Developed a fever to 38.4° C (101.2° F) Dapsone abruptly discontinued Did not have fever recurrence for the duration of hospitalization Diagnosis: Hospital Course • • • • • On HD 7, started on dapsone for pneumocystis prophylaxis Developed a fever to 38.4° C (101.2° F) Dapsone abruptly discontinued Did not have fever recurrence for the duration of hospitalization Diagnosis: drug-induced aseptic meningitis (DIAM) due to sulfa drugs Hospital Course • • • • • On HD 7, started on dapsone for pneumocystis prophylaxis Developed a fever to 38.4° C (101.2° F) Dapsone abruptly discontinued Did not have fever recurrence for the duration of hospitalization Diagnosis: drug-induced aseptic meningitis (DIAM) due to sulfa drugs – Dapsone, a sulfone, is structurally similar to sulfamethoxazole, a sulfonamide Discussion • DIAM is often associated with NSAIDs, antiepileptics, and other drugs – Diagnosis of exclusion – Well-documented with TMP-SMX • • • • • • Most frequently cited antibiotic Rapidly progressive Blood brain barrier Therapeutic levels in CSF for 15 hours First reported case in 1983, first reported in an HIV patient in 1994 Associated with autoimmune diseases and immunodeficiency/immunosuppression Repplinger et al. Am J Emerg Med (2011) 29,242.e3-242.e5. Thea et al. Infect Dis Clin North Am 1989;3:553-70. Dudley et al. Antimicrob Agents Chemother 1984;26:811-4. Discussion • Fever, headache, meningismus, mental status changes – – – – Confusion, coma, seizure ICU admission Intubation Global aphasia • Generally responds to withdrawal of offending agent • Continued/repeat ingestion has been shown to worsen symptoms Capra et al. Intensive Care Med. (2000) 26: 212-214. Repplinger et al. Am J Emerg Med (2011) 29,242.e3-242.e5. Harrison et al. Clin Infect Dis. 1994;19:431-4. Discussion • Proposed mechanism of action – Direct toxicity – Immunologic • Hypersensitivity reaction • Immune complex deposition • Auto-antibody induction • CSF analysis – Elevated protein – Elevated WBC – Normal or borderline glucose • Not reliable in differentiating from partially treated bacterial meningitis Von Reyn et al. Ann Intern Med 99: 342-344. River et al. J Neurol Neurosurg Psychiatry. 57: 705-708. Carillo et al. Rev Neurol 23 (119): 142-144. Capra et al. Intensive Care Med. (2000) 26: 212-214. Trimethoprim-induced aseptic meningitis in a patient with AIDS: case report and review • • • • 41 year old HIV+ treated with TMP-SMX for pneumocystis Suffered DIAM within hours of his first dose Promptly discontinued and symptoms resolved in 72 hours On day 14, treatment with TMP/Dapsone attempted – Dapsone given – 4 hours later, TMP given – 4 hours later, pt had recurrence of DIAM • Dapsone and TMP discontinued • 48 hours later patient returned to neurologic baseline • Felt to be due to TMP, as patient was followed on Dapsone pneumocystis prophylaxis for 6 months without issue Harrison et al. Clin Infect Dis. 1994;19:431-4. Conclusion • • • • DIAM in a patient with ICL Supported by use of sulfone antibiotic Aseptic nature does not denote a benign course Bacterial meningitis should remain high on differential diagnosis Resources • • • • • • • • • Walker UA, Warnatz K (July 2006). “Idiopathic CD4 lymphocytopenia”. Curr Opin Rheumatol 18 (4): 389–95. Thea D, Barza M. Use of antibacterial agents in infections of the central nervous system. Infect Dis Clin North Am 1989;3:553-70. Dudley MN, Levitz RE, Quintiliani R, et al. Pharmacokinetics of trimethoprim and sulfamethoxazole in serum and cerebrospinal fluid of adult patients with normal meninges. Antimicrob Agents Chemother 1984;26:811-4. Capra C, Monza GM, Meazza G, et al. Trimethoprim-sulfamethoxasole-induced aseptic meningitis: case report and literature review. Intensive Care Med 2000;26(2): 212-4. Repplinger MD, Falk PM. Trimethoprim-sulfamethoxazole-induced aseptic meningitis. Am J Emerg Med (2011) 29,242.e3-242.e5. Von Reyn CF (1988) Recurrent aseptic meningitis due to sulindac. Ann Intern Med 99. 343344. River Y, Averbuch-Heller L, Weinberger M, Meiner Z, Mevorach D, Schlesinger I, Argov Z (1994) Antibiotic induced meningitis. J Neurol Neurosurg Psychiatry. 57: 705-708. Carrilo F, Cubero A, Hernandez Gallego J Jimenez Santana P (1995) Recurrence of meningoencephalitis induced by cotrimoxazole. Rev Neurol 23 (119): 142-144. Harrison MS, Simonte SJ, Kauffman CA. Trimethoprim-induced aseptic meningitis in a patient with AIDS: case report and review. Clin Infect Dis. 1994;19(3):431-4. PRN Slides Healthy Individual with TMP/SMX DIAM Capra et al. Intensive Care Med. (2000) 26: 212-214. HIV patient withTMP/SMX DIAM * *and dapsone Harrison et al. Clin Infect Dis. 1994;19:431-4. CSF Bacterial Aseptic • Appearance • Appearance – Cloudy – Clear • Pressure • Pressure – 18-30 – 9-18 • WBC – 100-10,000 polys • Glc – <45 • TP – 100-1000 • WBC – <300 polyslymphs • Glc – 50-100 • TP – 50-100 BM Bx • 2003 – NORMOCELLULAR MARROW WITH MILD ERYTHROID AND MEGAKARYOCYTIC DYSPLASIA AND MEGALOBLASTOID CHANGES • This marrow is very small and hence, it is difficult to render a more definitive diagnosis. This marrow was compared with the previous marrow (NB02-200), which shows more severe leukopenia and thrombocytopenia, however, the rest of the marrow is more or less similar to the current marrow. The dysplasia does not show any increase in number or severity of changes. The presence of megaloblastoid changes and giant metamyelocytes suggest a B12 and/or folic acid deficiency. Close clinical follow-up and clinicopathologic correlation may be warranted. • 2007 – NORMOCELLULAR BONE MARROW WITH TRILINEAGE HEMATOPOIESIS AND INCREASED MONOLOBATED MEGAKARYOCYTES • Significant morphologic evidence of dysplasia is limited to the megakaryocytic lineage with greater than ten percent of megakaryocytes with hypo/monolobation. Significant erythroid dysplasia is not apparent. An evolving myelodysplastic disorder cannot be excluded. Correlation with cytogenetic studies and B12/folate levels is recommended.