Occam's razor need Occam's razor need not apply!not apply! ID Case ConferenceID Case Conference

Wednesday March 28, 2007Wednesday March 28, 2007David Fitzgerald, MDDavid Fitzgerald, MD

HPIHPI► 25 yo male immigrated from Guatemala 3 months ago now 25 yo male immigrated from Guatemala 3 months ago now

with complaints of fever, rash, abdominal pain and diarrhea with complaints of fever, rash, abdominal pain and diarrhea for the last 3 months since arriving in the US. These sxs have for the last 3 months since arriving in the US. These sxs have worsened over the last 2 weeks prompting his presentation to worsened over the last 2 weeks prompting his presentation to the ER. Describes abd pain as diffuse and crampy. Diarrhea the ER. Describes abd pain as diffuse and crampy. Diarrhea is currently watery but had been bloody initially.is currently watery but had been bloody initially.

► Three months ago he walked across the desert border in Three months ago he walked across the desert border in Arizona and spent 8 days in the desert short of water and Arizona and spent 8 days in the desert short of water and food. After a few days he began to have bloody BM's. No prior food. After a few days he began to have bloody BM's. No prior episodes of bloody BM's.episodes of bloody BM's.

► He saw a doctor recently and was given Aciphex for reflux and He saw a doctor recently and was given Aciphex for reflux and a Medrol dose pack for the rash. He was also given an a Medrol dose pack for the rash. He was also given an unknown injection.unknown injection.

► In ER pt had temp to 39.1, was tachycardiac and hypotensive. In ER pt had temp to 39.1, was tachycardiac and hypotensive. S/p 8 L of fluid in ER and remained with tachycardia and S/p 8 L of fluid in ER and remained with tachycardia and borderline BP. Increasing O2 requirement as well. Admitted to borderline BP. Increasing O2 requirement as well. Admitted to MICU.MICU.

► PMHPMH Reports history of Reports history of

eye surgery as a eye surgery as a childchild

► SHSH Recent immigrant from Recent immigrant from

Guatamala as above. Guatamala as above. Married, wife and 15 Married, wife and 15 month old son in month old son in Guatamala. Both are well.Guatamala. Both are well.

Lives with his wife’s cousin Lives with his wife’s cousin and several other friendsand several other friends

Works at McDonaldsWorks at McDonalds Denies ETOH, tobacco or Denies ETOH, tobacco or

illicit drugsillicit drugs Travel history across Travel history across

desert southwest.desert southwest.

► FHFH NCNC

►MedsMeds AcidphexAcidphex

ROSROS► Gen – fevers, chills, mild NS. 15 Lb wt loss over last 3 monthsGen – fevers, chills, mild NS. 15 Lb wt loss over last 3 months► Neuro- No HA, neck stiffness, visual changes, focal weakness Neuro- No HA, neck stiffness, visual changes, focal weakness

or confusion. Friends with him confirm no change in mental or confusion. Friends with him confirm no change in mental statusstatus

► HEENT – denies oral lesions, dysphagia/odynophagia, visual HEENT – denies oral lesions, dysphagia/odynophagia, visual disturbancesdisturbances

► CV – no cp/palpsCV – no cp/palps► Pulm – mild cough, non productive. No SOBPulm – mild cough, non productive. No SOB► GI- as above with diarrhea, abd pain. No vomiting, mild GI- as above with diarrhea, abd pain. No vomiting, mild

nausea.nausea.► Gu- no ulcers, discharge or dysuriaGu- no ulcers, discharge or dysuria► Skin – nonpruritic pink rash that started on his face, moved to Skin – nonpruritic pink rash that started on his face, moved to

his trunk and stomach and then to his arms and legs.his trunk and stomach and then to his arms and legs.

Physical examPhysical exam► Temp : Temp : 39.139.1 Pulse:115 RR:20 Pulse:115 RR:20 ► BP 115/70, Sat: 95-98% 2 LBP 115/70, Sat: 95-98% 2 L► GeneralGeneral: Pleasant : Pleasant

interactive, thin, Hispanic interactive, thin, Hispanic male, in mild distressmale, in mild distress

► HEENTHEENT – PERRLA, EOMI, – PERRLA, EOMI, Anicteric, mild conj injection Anicteric, mild conj injection bilaterally,bilaterally, MM dry. No oral lesions or MM dry. No oral lesions or

thrushthrush► NeckNeck – supple – supple► LymphLymph – no cervical, – no cervical,

supraclavicular, axillary or supraclavicular, axillary or inguinal LAN notedinguinal LAN noted

► CVCV -Tachy, regular, no mrg -Tachy, regular, no mrg► LungLung – bronchial BS at bases – bronchial BS at bases

bilaterally. Mild crackles bilaterally. Mild crackles aboveabove

► AbdAbd – soft, mild ttp in R UQ – soft, mild ttp in R UQ and RLQ, + BS, and RLQ, + BS, nondistended. No nondistended. No RB/Guarding.RB/Guarding.

► GU-GU- no lesions or discharge no lesions or discharge► ExtExt – no c/c/e – no c/c/e► SkinSkin

Confluent, non-tender, Confluent, non-tender, blanchable macular erythema blanchable macular erythema on the face and upper trunk.on the face and upper trunk.

Maculopapular, non-tender, Maculopapular, non-tender, blanchable erythema, blanchable erythema, proximal>distal extremities. proximal>distal extremities.

► Neuro:Neuro: A+O x 3, non focal A+O x 3, non focal strength and sensation strength and sensation grossly, CN2-12 intactgrossly, CN2-12 intact

DataData► WBC 14.0WBC 14.0

ANC 12.2ANC 12.2 ALC 0.4ALC 0.4

► HGB 10.2 (decreased to 8.0 then HGB 10.2 (decreased to 8.0 then to 7.3 over 12 hours)to 7.3 over 12 hours) MCV 78MCV 78 RDW 16RDW 16 Retic count - 0.5% (low)Retic count - 0.5% (low) Spherocytes notedSpherocytes noted Howell Jolly bodies notedHowell Jolly bodies noted

► PLT 395PLT 395

► PT 19.4 INR 1.6 PTT 44PT 19.4 INR 1.6 PTT 44► D dimer – 56,000D dimer – 56,000► LDH – 20,000LDH – 20,000► Fibrinogen 303Fibrinogen 303► AT III 82% lowAT III 82% low

► Direct Coombs Direct Coombs Anti IgG - positiveAnti IgG - positive Anti-complement negativeAnti-complement negative

► Na 132 Na 132 ► K 4.7 K 4.7 ► Cl 98 Cl 98 ► HCO3 20HCO3 20► BUN/Cr 18/1.1BUN/Cr 18/1.1► Ca 6.0Ca 6.0► Mg 1.9Mg 1.9► PO4 4.4PO4 4.4

► LFTSLFTS► Tbili 0.6Tbili 0.6► AST 580AST 580► ALT 106ALT 106► Alk Phos 622Alk Phos 622► GGT 339GGT 339

DATADATA

► CRP 17.6CRP 17.6

► UA LE and Nit Neg, 2+ protein, UA LE and Nit Neg, 2+ protein, WBC 6, RBC 7WBC 6, RBC 7

► Tox screen – negativeTox screen – negative

► CK 95CK 95

► CSFCSF TNC 2 TNC 2

►38% PMNS38% PMNS►25% Lymphs25% Lymphs

RBC <1RBC <1 Protein 32Protein 32 Glucose 59Glucose 59

RadiologyRadiology

► CT chest and CT chest and abdomen abdomen 1. Patchy nodular 1. Patchy nodular

parenchymal parenchymal opacifications are opacifications are concerning for concerning for infectious pneumonitis. infectious pneumonitis.

2. Inflammatory change 2. Inflammatory change of the ascending colon of the ascending colon with adjacent free fluid with adjacent free fluid suggests infectious suggests infectious colitis. colitis.

► RUQ US – negative RUQ US – negative for cholecystitis. for cholecystitis. Nml liver, spleen Nml liver, spleen and kidneysand kidneys

Peripheral smearPeripheral smear

DiagnosesDiagnoses

► Fungal – HistoFungal – Histo Peripheral blood smear – Peripheral blood smear –

intracellular and intracellular and extracellular yeast notedextracellular yeast noted

CSF cell count – CSF cell count – intracellular yeast notedintracellular yeast noted

Urine histo ag +Urine histo ag +

► BacteremiaBacteremia Blood cx – Blood cx –

► 1. Strep Pneumonia1. Strep Pneumonia► 2. E coli2. E coli

► Viral – HIV, EBV, CMVViral – HIV, EBV, CMV HIV Elisa +HIV Elisa + EBV VL - 32,308EBV VL - 32,308 CMV VL – 3876CMV VL – 3876

► ParasiticParasitic Fecal cx – 4+ PMNsFecal cx – 4+ PMNs Fecal O+P –Entamoeba Fecal O+P –Entamoeba

histolyticahistolytica► Negative studiesNegative studies

Hepatitis serologies Hepatitis serologies negativenegative

Bronch – PCP DFA Bronch – PCP DFA negativenegative

CSF – CSF – ► HSV PCR negHSV PCR neg► Crypto ag negCrypto ag neg

Final diagnosis Final diagnosis

►Disseminated histoplasmosis with Disseminated histoplasmosis with meningitismeningitis

►HIV (CD4<10)HIV (CD4<10)►CMV viremia (? Colitis)CMV viremia (? Colitis)►EBV viremia (? Underlying lymphoma)EBV viremia (? Underlying lymphoma)►Entamoeba histolyticaEntamoeba histolytica►Strep Pna and E coli bacteremiaStrep Pna and E coli bacteremia►Hemolytic anemiaHemolytic anemia

Warm antibody autoimmune Warm antibody autoimmune hemolytic anemia (AIHA)hemolytic anemia (AIHA)

► Autoimmune hemolytic Autoimmune hemolytic anemia (AIHA) due to anemia (AIHA) due to the presence of warm the presence of warm agglutinins is due to agglutinins is due to IgG antibodies that IgG antibodies that react with protein react with protein antigens on the red antigens on the red blood cell (RBC) surface blood cell (RBC) surface at body temperature. at body temperature.

► For this reason, they For this reason, they are called "warm are called "warm agglutinins" even agglutinins" even though they seldom though they seldom directly agglutinate the directly agglutinate the RBCs. RBCs.

► Various etiologies – Various etiologies – Drugs (penicillin, methyl-Drugs (penicillin, methyl-

dopa, huge list)dopa, huge list)► Infectious agents – Infectious agents –

usually viralusually viral► Neoplasms (NHL and Neoplasms (NHL and

CLL)CLL)► autoimmune disease autoimmune disease

(esp SLE)(esp SLE)► Idiopathic (majority)Idiopathic (majority)

AIHA – extravascular AIHA – extravascular hemolysishemolysis

►Results in extravascular hemolysis in Results in extravascular hemolysis in spleen as deformed RBC (spherocytes) spleen as deformed RBC (spherocytes) are unable to fit through the slits in are unable to fit through the slits in the walls of the blind channels in the the walls of the blind channels in the cords of Billroth cords of Billroth

DiagnosisDiagnosis

► Hemoglobin usually in the Hemoglobin usually in the range of 7 to 10 g/dL range of 7 to 10 g/dL

► Positive Direct Coombs test Positive Direct Coombs test – detects the presence of – detects the presence of IgG or complement bound IgG or complement bound to erythrocyte mebranes to erythrocyte mebranes

► Retic count usually elevated Retic count usually elevated above 4 to 5 percent above 4 to 5 percent

► LDH elevatedLDH elevated► Indirect Bilirubin elevatedIndirect Bilirubin elevated► Haptoglobin decreasedHaptoglobin decreased► Peripheral blood smear Peripheral blood smear

usually shows the presence usually shows the presence of spherocytosis of spherocytosis

► The combination of an The combination of an increased serum LDH and increased serum LDH and reduced haptoglobin is 90 reduced haptoglobin is 90 percent specific for percent specific for diagnosing hemolysis, while diagnosing hemolysis, while the combination of a normal the combination of a normal serum LDH and a serum serum LDH and a serum haptoglobin greater than 25 haptoglobin greater than 25 mg/dL is 92 percent mg/dL is 92 percent sensitive for ruling out sensitive for ruling out hemolysis hemolysis

► Diff dx is that of hemolytic Diff dx is that of hemolytic anemia due to drugs and anemia due to drugs and AIHA due to the presence of AIHA due to the presence of cold agglutinins (IgM)cold agglutinins (IgM)

ComplicationsComplications

► Lymphoproliferative Lymphoproliferative disorder disorder In one series of 108 In one series of 108

patients (not HIV) patients (not HIV) 18% developed a 18% developed a lymphoproliferative lymphoproliferative disorder after a disorder after a median time of 2 median time of 2 yearsyears

► Venous Venous thromboembolism thromboembolism Reported in both Reported in both

Non-HIV and HIV Non-HIV and HIV patientspatients

AIHA in HIV/AIDSAIHA in HIV/AIDS

► Direct Coombs test is positive in 20-40% of AIDS Direct Coombs test is positive in 20-40% of AIDS patients but overt hemolysis is rarepatients but overt hemolysis is rare

► Not well studied area due to small numbers of Not well studied area due to small numbers of cases reportedcases reported

► Pathophysiology of AIHA in AIDS may be related to Pathophysiology of AIHA in AIDS may be related to Hypergammaglobulinemia related to B-Cell dysregulationHypergammaglobulinemia related to B-Cell dysregulation Direct activation of B cells by HIVDirect activation of B cells by HIV Coinfection with EBV or CMVCoinfection with EBV or CMV Other infectious agents associated with AIDS may also be Other infectious agents associated with AIDS may also be

associated with production of auto-antibodiesassociated with production of auto-antibodies► MAI, CMV, EBV, PCP, M TB, Histoplasma capsulatiumMAI, CMV, EBV, PCP, M TB, Histoplasma capsulatium

AIDS related malignanciesAIDS related malignancies

Reticulocytopenia Reticulocytopenia

► Reticulocytopenia in AIHA is more common in Reticulocytopenia in AIHA is more common in HIV patients than in the general populationHIV patients than in the general population

►May lead to underdiagnosis of AIHA in HIV May lead to underdiagnosis of AIHA in HIV patientspatients

► TheoriesTheories May be due to antibodies that preferentially May be due to antibodies that preferentially

destroy reticulocyte precursors destroy reticulocyte precursors May be related to abnormal microenvironment in May be related to abnormal microenvironment in

bone marrow caused by other infections (MAI, bone marrow caused by other infections (MAI, Histo, CMV), lymphoma or drugs (ZDV)Histo, CMV), lymphoma or drugs (ZDV)

TreatmentTreatment

► No great data on the efficacy of various modalitiesNo great data on the efficacy of various modalities► Patients with + Coombs, stable HGB and only mild Patients with + Coombs, stable HGB and only mild

hemolysis can be monitoredhemolysis can be monitored► Transfusions – may be difficult to cross matchTransfusions – may be difficult to cross match► Corticosteroids – mainstay of treatment.Corticosteroids – mainstay of treatment.

Prednisone 1 mg/kg dailyPrednisone 1 mg/kg daily Quickly slows or stops hemolysis in up to 2/3 of patients Quickly slows or stops hemolysis in up to 2/3 of patients

and results in increase in HGB within one weekand results in increase in HGB within one week Once stabilized can start taperOnce stabilized can start taper

► IVIG – best used with steroids. IVIG – best used with steroids. Used in severe cases when a rapid response is desired Used in severe cases when a rapid response is desired 1 g/kg per day for 2 days1 g/kg per day for 2 days May decrease infectious complications of steroidsMay decrease infectious complications of steroids

TreatmentTreatment► SplenectomySplenectomy

75% success rate in HIV patients with AIHA75% success rate in HIV patients with AIHA Removes the major site of RBC destructionRemoves the major site of RBC destruction Recommended in patients who do not respond to steroids or Recommended in patients who do not respond to steroids or

cannot be tapered off themcannot be tapered off them Can increase the number of circulating CD4 cells, but not alter Can increase the number of circulating CD4 cells, but not alter

the ratiothe ratio► ImmunosuppressivesImmunosuppressives

Not universally accepted, even in those who fail to respond to Not universally accepted, even in those who fail to respond to above treatmentsabove treatments

Can lead to worsening of anemia by BM suppressionCan lead to worsening of anemia by BM suppression► Plasmapheresis Plasmapheresis

ControversialControversial Due to the large extravascular distribution of IgG and continued Due to the large extravascular distribution of IgG and continued

AB productionAB production

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►Autoimmune Hemolytic Anemia (AHIA)Autoimmune Hemolytic Anemia (AHIA) Case ReportsCase Reports ReviewsReviews Differential DiagnosisDifferential Diagnosis Drug TherapyDrug Therapy