BRIEF CLINICAL OBSERVATIONS

suggestive of procainamide-induced DIL [3]. Bare pleuropulmonary manifestations of procainamide-induced DIL include persistentrestrictive lung disease with reduced diffusion capacity [3], pulmonary thromboembolism due to anticardiolipin antibodies [4], and interstitial neutrophilic alveolitis [5]. Massive pericardial effusion as well as constrictive pericarditis without effusion resulting in cardiactamponade has also been reported [3,6]. Interestingly, we havebeen unable to find reporta of a resistant pleural effusion requiring pleurectomy or intrapleural tetracycline in procainamide-induced DIL, which has been reported in natural SLE [7]. We are unaware of other reports of reversible pleural fibrosis without effusion, which was the case in our patient. We suggestthat this clinical entity should be addedto the spectrum of procainamideinduced DIL. SHABB~RSHEIKH,~~.~.D. JORAMS.SEGGEV,MD.

University of Missouri-Columbia and Harry S. Truman Memorial Veterans Affairs Hospital Columbia, Missouri 1. Weinstein A. Drug-induced systemic lupus erythematosus. Prog Clin lmmunol 1980; 4: 1-21. P.Cush JJ. Geldings EA. Southwestern Internal Medicine Conference: Drug-induced lupus: clinical spectrum and pathogenesis. Am J Med Sci 1985; 290: 36-44. 3. Ginsburg WW. Drug-induced systemic lupus erythematosus. Clin Respir Med 1980; 2: 51-8. 4. Asherson RA. Zulman J, Hughes GRV. Pulmonary thromboembolism associated with proceinamideinduced lupus syndrome and anticardiolipin antibodies. Ann Rheum Dis 1989; 48 232-5. 5. Goldberg SK, Lipschutz JB, Ridcetts RM. Fein AM. Procainamide-induced lupus lung disease characterized by neutrophil alveolitis. Am J bled 1% 76: 14640. 6. Browning CA, Bishop RL, Heilpern RI. Singh JB, Spodick DH. Accelerated constrictive pericarditis in procainamide-induced systemic lupus erythematosm.. Am J Cardiol 1984; 53: 376-7. 7. Gilleece MH, Evans CC, BucknaIl RC. Steroid resistant pleural effusion in systemic lupus erythematosus treated with tetracycline pleurodesis. Ann Rheum Dis 1988; 47: 1031-2. Submitted

February

20, 1991. and accepted in revised form April 16, 1991

PHENAZOPYRIDINE=INDUCED bin level had not fallen. The paSULFHEMOGLOBINEMIA: tient’s hemoglobin level deINADVERTENTRECHALLENGE creased to 8.6 g/dL, requiring transfusion of 2 units of packed Phenazopyridine hydrochloride red blood cells.The lactate dehy(Pyridium) exerts analgesic ac- drogenase and bilirubin levels tion on the urinary tract mucosa. werenormal and the reticulocyte This axedye is usedcommonly in index was 1.8%.Nine days after clinical practice with few adverse admission, her methemoglobin side effects. The present report level had decreasedto 26.5%and describesa patient who, while re- shewasdischargedreceivingnorceiving usual dosesof phenazo- floxacin, furosemide, and potaspyridine, developedsulfhemoglo- sium chloride. Thirteen days afbinemia, ter discharge, her methemogloAn &year-old woman wasad- bin level was 12%. mitted to the hospital complainNine months later, she was ing of dizziness.A recent urinary seenby her local physician for a infection had prompted her lacerated forearm. Bacteruria physician to initiate treatment prompted treatment with sulfawith nitrofurantoin and phenazo- methoxaxole/trimethoprim and, pyridine (100mg four times dai- inadvertently, phenazopyridine ly). Physical examination re- (100 mg four times daily). She vealedcyanosisand yellow stain- was admitted to the hospital 1 ing of her lega; she had had a weeklater for cyanosisand a fracFoley catheter for several years tured humerus. Her hemoglobin becauseof urinary incontinence. level was 12.9 g/dL and metheLaboratory studies revealed a moglobin value 30%.Shereceived white blood cell count of 14,700/ methylene blue (2 mg/kg intravemm3, hemoglobin level of 12.6 nously over 5 minutes) on two ocg/dL, blood ureanitrogen level of casions with no change in her 14 mg/dL, creatinine value of 1.0 methemoglobin level. Urine grew mg/dL, and a glucose-6-phos- nitrite-producing Pseudomonas phate dehydrogenase (GGPD) aeruginosa and group D enterovalue of 275 U/1O12red blood coccus. Discharge occurred 13 cells (normal 146 to 376 U/1012 dayslater with the patient’s metred blood cells). A urine culture hemoglobin level at 19.8%.Eight grewnitrite-producing organisms months later, her methemoglobin (Escherichia coti, Proteus miralevel was 2.2%as an outpatient. biEis, group D enterococcus). Phenazopyridine hydrochloA Co-oximeter panel was ob- ride, a popularurinary tract analtained (IL 482 Co-oximeter Sys- gesic,hasfew seriousside effects. tem, Instrumentation Laborato- These include methemoglobinery, Lexington, Massachusetts) mia, hemolysis, acute renal failwith a methemoglobin value of ure, and yellow skin pigmenta50.3%.This system doesnot dif- tion; most occur in patients takferentiate betweenmethemoglo- ing a higher than recommended bin and s&hemoglobin and com- doseor in thosewith impaired reputes only the methemoglobin nal function [l-3]. Our report value.The addition of sodium cy- concernsa patient with normal anide to the patient’s blood sam- renal function who developed ple demonstrated no change in sulfhemoglobinemiawhile taking methemoglobin. Methylene blue usual doses. (2 mg/kg) wasgiven intravenousThe laboratory documentation ly over 5 minutes. Onehour later, of s&hemoglobin requires speanother dose of methylene blue cial facilities that were not availwas given sincethe methemoglo- able to us; therefore,our proof is September 1991 The American Journal of Medicine

Volume 91

315

BRIEF CLINICAL OBSERVATIONS

40

60

Time

00

100

120

(days)

60

SO

B

40 3 e $f 30

2

20 10

0

Time (days)

Figure

1. Superimposition of normal erythrocyte lifespan curve with the patient’s methemoglobin (Met Hb) values. The erythrocyte lifespan curve is derived from 51Cr-labeling techniques [9]. In a normal person, the survival curve is’ exponential (half-life about 30 days) and finite (about 120 days) with this technique. The curves are similar but not identical. This is particularly evident during the first hospitalization (A) and due in part to the transfusion of 2 units of packed red blood cells (RBCs) on the fourth day of hospitalization. The patient did not receive any blood during the second hospitalization (B), with the curves running more parallel.

circumstantial. First, the spectral absorbance of sulfhemoglobin and methemoglobin is similar (620 nm). Advantage is taken of the fact that the methemoglobin band disappearswith the addition of cyanide [4,5]. In our patient’s blood samples,the methemoglobin level did not decrease with the addition of cyanide, which suggeststhe presenceof sulfhemoglobin. Second, in patients with normal GGPD levels, intravenousmethylene blue substitutes as a cofactor in the alternate methemoglobin reduction pathway involving NADPH from the pentoae-phoephate shunt. No change in the methemoglobin level after two dosesof methylene 316

blue suggests the presence of sulfhemoglobinemia [6]. Third, the reconversionof methemoglobin to hemoglobin occurswithin hour8 following the removal of the offending agent [3,6].In contrast, sulfhemoglobin cannot be convertedback to hemoglobin;it persistsuntil the erythrocytecarrying the abnormal pigment reachesthe end of its lifespan [4,6].The superimposition of our patient’s methemoglobin values and normal erythrocyte lifespan curves is similar, which suggests the presenceof s&hemoglobin (Figure

1).

It is unlikely that nitrite-producing pathogenscould explain our patient’s sulfhemoglobine-

September 1991 The American Journal of Medicine

Volume 91

mia. One would have to assume that thesepathogenshad not existed prior to or after thesehospitalizations when, in fact, there had been previous urinary infections During a subsequenthospitalization in which nitrite-producing Klebsiella pneumoniae and group D enterococcuawere obtainedfrom her urine (shewas not taking phenazopyridine),the methemoglobin value was normal. Despite widespreaduse,phenasopyridinerarely producesserioussideeffects [2]. There is, however, a report of a patient who receiveda combination of phenazopyridine/sulfisoxaxoleand developed sulfhemoglobinemia demonstrated by spectrophotometric analysis[i’] . Oneother patient had hemolytic anemia and sulfhemoglobin while taking phenoylazo-diamino-pyridine [8]. The present report supports the notion that phenaxopyridine can producesulfhemoglobinemia and should be consideredin the differential diagnosisin a patient whois taking this medication and develop8cyanosis. SHEILA M.HALvoRsEN,P~~~~.D. University of Iowa College of Pharmacy Iowa City, Iowa WILLIAML. DULL,M.D. Iowa City, Iowa 1. Alano FA, Webster DG Jr. Acute renal failure and pigmentation due to phenazopyridine (Pyridium). Ann Intern Med 1970; 72: 89-91. 2. Green ED, Zimmerman RL, Ghurabi WH, Colohan DP. Phenazopyridine hydrochloride toxicity: a cause of drug-induced methemoglobinemia. JACEP 1979; 8: 426-31. 3. Nathan DM, Siegel Al, Bunn F. Acute methemoglobinemia and hemolytic anemia with phenazopyridine. Arch Intern Med 1977; 137: 16368. 4. Beutler E. Methemoglobinemia and sulfhemoglobinemia. In: Williams WJ, Beutler E, Erslev Al, Lichtman MA, editors. Hematology. 4th ed. New York: McGraw-Hill, 1990: 7436. 5. Park CM, Nagel RL. Sulfhemoglobinemia: clinical and molecular aspects. N Engl J Med 1984; 310: 1579-84. 6. Donovan JW. Methemoglobinemia. In: Haddad LM. Winchester JF. editors. Clinical management of poisoning and drug overdose. Philadelphia: WB Saunders, 1983: 905-9. 7. Lim TPK. Lower D. “Enterogenous” cyanosis. Am Rev Respir Dis 1970; 101: 419-22.

8. Gabor EP, Lowenstein L, DeLeeuw NKM. Hemolytic anemia induced by phenylazodiimino-pyridine (Pyridium). Can Med Assoc J 1964; 91: 756-9. 9. Erslev AJ. Erythrokinetics. In: Williams WJ,

Beutler E, Erslev AJ. Lichtman MA, editors. tology. 4th ed. New York: McGraw-Hill, 414-22. Submitted

September

GM-CGF 0.3 $Kg/dly

Hemb 1990: 2//”

24, 1990, and accepted in revised form March 13, 1991

(NOTE: We wish to acknowledge S.F. Palmer,

&

the assistance

i

of

-4

M.D.)

TREATMENT OF CYCLIC NEUTROPENIAWITH VERY LOWDOSESOF GM-CSF In cyclic neutropenia, periods of severeneutropenia (nadir count lessthan 200FL) recur about every 3 weeksand may be complicatedby fever,stomatitis, and infection [11.Recently, granulocyte colony-stimulating factor (GCSF) has been successfullyused to treat this disorder as well as other chronic neutropenias such a8 Kostmann syndrome [2-5]; in contrast, in these syndromes, granulocyte macrophage-CSF (GM-CSF), at dosesgreaterthan or equal to 3 r(g/kg/day,has been reportedto markedly increaseeosinophil counts without a salutary effect on neutrophils [2,5]. Because we have recently observed beneficial effects associated with administration of GMCSF at dosesfar lower than are standard [6,7], we treated a patient who had cyclic neutropenia with 0.3 fig/kg/day (12 rg/ m2/day) of GM-CSF injected subcutaneously. Before treatment, neutropenic episodes in this patient were complicated by repeated infections and severe oropharyngeal ulcers necessitating multiple hospitalizations. Very-low-dose GM-CSF treatment abolished the neutropenia and completely resolved the infections, stomatitis, and malaise. A 30-year-old patient was referred to us for management of cyclic neutropenia. She was first diagnosed5 years earlier. An attempt at corticosteroid therapy

Days Figure 1. Absolute neutrophil counts of the patient with cyclic neutropenia. A typical pretherapy cycle is depicted. The patient had regular cycles for 5 years. Selected neutrophil counts ed. No further neutrophil

during nadirs

the 4 months were noted.

wasabortedbecauseof a psychotic reaction. Over the subsequent years,she noted moderate to severe fatigue accompaniedby oral ulcersand fever for approximately 7 to 10 days out of every 3 weeks.Indeed, shehad beenhospitalized 11 times for high fever and severe oropharyngitis leading to poor oral intake during the neutropenic episodes. Neither she nor her family (including her three children) is afflicted by any other chronic medical disorder. Result8 of physical examination at the time of referral were unremarkable, other than for severalulcers on the buccal mucosa. Laboratory test8 revealed that platelet counts and hemoglobin levels were consistently normal. The pattern of neutrophi1counts is shown in Figure 1. It should be noted that neutropenic episodeslasted for about 7 day8and recurredevery 3 weeks, and nadir neutrophil levels were below 100cells/pL. Results of renal and liver function tests, vitamin Bi8 and red blood cell folate levels,and quantitative immunoglobulin levels were within normal limits. There were no antineutrophil antibodies, as asSeptember

1991

The American

of GM-CSF

therapy

are

also

present-

sessedby indirect immunofluorescence.Test8 for antinuclear antibodies, rheumatoid factor, and human immunodeficiency virus antibody were all negative. A bonemarrow aspiration and biopsywereperformed and showed 50% cellularity with a relatively high proportion of myelocytes and metamyelocytes but no significant morphologic abnormality. A previousbone marrow had, however, shown myeloid hyperplasia with a shift to the left. Chromosomeanalysison 25 bone marrow metaphases demonstrated a normal female karyotype. After informed consentwasobtained according to our institutional guidelines, GM-CSF (Schering-SandozResearchCorporation), 0.3gg/kg/day subcutaneously(1yg/kg is approximately equivalent to 40 rg/m2), was started. Her clinical courseis depicted in Figure 1. She has now been receiving continuous treatment for 4 months. Her absolute neutrophil counts are generally in the rangeof 2,00O/~Lwithout cycling. She has discontinued oral antibiotics, and hashad complete resolution of stomatitis, feJournal

of Medicine

Volume

91

317