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Myiasis Due to Hypoderma lineatum Infection Mimicking the Hypereosinophilic Syndrome

      Myiasis is the infestation of live humans with larvae of Diptera (true flies). This report describes a protracted illness caused by infestation with Hypoderma lineatum, resembling the hypereosinophilic syndrome. A 35-year-old man had a 9-month multisystemic illness with pronounced eosinophilia, pleuritis, pericarditis, and myositis. Treatments including glucocorticoids did not alter the disease. Diagnostic studies included computed tomography, 2-dimensional echocardiograpby, leukocyte count, surgical biopsy of skin and muscle, blood immunoglobulin levels, and blood chemistry. Myiasis was recognized when a worm emerged from the patient's skin; after a second worm emerged, the patient's symptoms disappeared rapidly. Other determinations included IgE and IgG levels specific for H lineatum, Western blot, and immunofluorescence for eosinophil major basic protein; IgG antibodies to H lineatum decreased after emergence of the worms. The patient's symptoms mimicked the hypereosinophilic syndrome but resolved when the myiasis became apparent. Specific serologic analyses can identify infected patients, and ivermectin may be useful as treatment.
      CT (computed tomography), ELISA (enzyme-linked immunosorbent assay), HL1 (extract of Hypoderma lineatum first instar larvae), MBP (major basic protein)
      Myiasis is the infestation of live human or other vertebrate animals with larvae of Diptera (true flies). The ancient Romans knew about the serious economic effects of myiasis caused by cattle grubs on skins intended for leather manufacture.
      • Beesley WN
      The myiases.
      Fifty Fifty species of Diptera produce myiasis in humans, and most are unimportant; however, several cause serious lesions. For example, larvae from Hypoderma lineatum are hatched from eggs laid on hair, can penetrate unbroken skin through the follicles, feed on internal tissues, and migrate in the first instar stage.
      • Beesley WN
      The myiases.
      During such infestations, massive blood and tissue eosinophilia and a condition resembling the hypereosinophilic syndrome can develop.
      • Uttamchandani RB
      • Trigo LM
      • Poppiti Jr, RJ
      • Rozen S
      • Ratzan KR
      Eosinophilic pleural effusion in cutaneous myiasis.
      We describe a 35-year-old man who had a protracted multisystemic illness with pronounced eosinophilia, pleuritis, pericarditis, and myositis. When a maggot emerged from his skin, myiasis was diagnosed. This malady should be considered in the differential diagnosis of several syndromes associated with eosinophilia, including the hypereosinophilic syndrome.

      Report Of A Case

      A 35-year-old cattle rancher and oil field worker in Texas was healthy until March 1995, when he noted gradual onset of bilateral arm and shoulder pain, as well as back and chest discomfort. Additionally, cough and chest tightness occurred, but he had no wheezing. Symptoms persisted after glucocorticoid and doxycycline treatment. In June 1995, right upper quadrant abdominal discomfort and nausea developed. Further treatment included H2 blockers and a proton pump inhibitor. Findings on upper gastrointestinal tract radiography, gallbladder ultrasonography, and esophagoduodenoscopy were normal; Trichinella antibody and stool test results for parasites were negative. During August and September 1995, the patient developed night sweats, chills, rigors, and intermittent fever (temperature up to 39°C). Severe diffuse myalgia occurred, and pleural and pericardial rubs were heard. Computed tomography (CT) of the chest disclosed bilateral pleural effusions and a moderatesized pericardial effusion. A complete blood cell count yielded 16.7 × 109/L leukocytes (reference ranges shown parenthetically) (3.5–10.5 × 109/L) with 48% eosinophils. Two-dimensional echocardiography confirmed the peri­ cardial effusion but otherwise showed normal findings. By mid-September 1995, the left-sided pleural effusion had increased, and thoracentesis yielded an exudate containing 1% eosinophils. At that time, swelling and tenderness of the patient's left testicle developed. Still disease was diagnosed and treated with aspirin. Symptoms persisted, and he was hospitalized. His leukocyte count was 27.4 × 109/L, with 32% eosinophils. Repeated leukocyte counts ranged from 16.8 to 30.0 × 109/L with the absolute eosinophil numbers varying from 8.0 to 22.6 × l0
      • Cogley TP
      • Anderson JR
      • Weintraub J
      Ultrastructure and function of the attachment organ of warble fly eggs (Diptera: Oestridac: Hypodermatinae).
      /L (0.05–0.5 × 109/ L). Results of a rheumatoid factor latex test were elevated at 80.2 IU/mL (0–19 IU/mL); the alkaline phosphatase level was slightly elevated. A second chest CT scan showed small pleural effusions and a tiny pericardial effusion. Abnormal fluid accumulation occurred in the right upper posterior chest tissue planes; later, pronounced swelling developed in this area. In early October 1995, surgical biopsy of the latissimus dorsi and overlying skin showed severe inflammation and eosinophilic infiltration; no parasites were detected. Nonsteroidal anti-inflammatory drugs provided no improvement. In mid-October 1995, the patient's IgE was 1547 kU/L (0–240 kU/L), IgG was 1480 mg/dL (700–1500 mg/dL.), IgA was 317 mg/dL (60–400 mg/dL), IgM was 111 mg/dL (60–300 mg/dL), and the erythrocyte sedimentation rate was 30 mm/l h (0–20 mm/l h). Late in October, small pruritic nodules appeared on the back of the patient's legs and around his waist, persisting for 4 to 7 days. A biopsy specimen from a right posterior thigh lesion disclosed perivascular infiltration with eosinophils and mononuclear cells. After the overall clinical picture was reviewed, the hypereosinophilic syndrome was diagnosed, and prednisone was initiated at 60 mg/d. A month later, while receiving prednisone every other day, the patient continued to have urticaria, modest eosinophilia (12%), and a leukocyte count of 10.0 × 109/L. Two months later, on December 18, 1995, a new skin lesion developed on the patient's lower abdominal area. When he rubbed this lesion, a white worm (about 1 em long) emerged (Figure 1). This larva was H lineatum, second instar stage. The prednisone dosage was rapidly reduced and discontinued. Two weeks later, a second larva exited from a skin lesion on the patient's back-The patient's symptoms disappeared rapidly; 3 weeks later he had normal numbers of eosinophils.
      Figure thumbnail gr1
      Figure 1Second instar stage of Hypoderma lineatum. The white larva was about 1 cm long and 0.15 cm in diameter. It emerged from the patient's skin on December 18, 1995. Morphologic identification was based on distinctive features in the spircular plate (the breathing apparatus on the posterior end) to distinguish between the species and larval stage.

      Histological Analyses

      Surgical biopsy specimens were analyzed for eosinophil granule major basic protein (MBP) by using a previously described indirect immunofluorescence assay.
      • Peters MS
      • Schroeter AL
      • Kephart GM
      • Gleich GJ
      Loc-alization of eosinophil granule major basic protein in chronic urticaria.
      Extensive extracellular MBP deposition was noted between muscle bundles and in disrupted fascia with few intact eosinophils (Figure 2). Staining with hematoxylin-eosin showed extensive perivascular and interstitial inflammation with few eosinophils; the muscle fibers were well preserved. Serial sections stained with normal rabbit IgG were negative.
      Figure thumbnail gr2
      Figure 2Immunofluorescent localization of eosinophil granule major basic protein (MBP) in surgical muscle biopsy specimens (A and C). Sections were stained with affinity-purified rabbit antihuman MBP (B and D). Hematoxylin-eosin (H&E) counterstains of the same areas are shown in A and C, respectively. Extensive extracellular MBP deposition was present between muscle bundles (A); however, intact eosinophils were not evident on the H&E counterstain of the same area (B). In another area from the same biopsy specimen, striking extracellular MBP deposition was also noted in disrupted fascia (C); few eosinophils were observed in the H&E counterstain of the same area (D). (A-D, original magnification, ×400.)

      Detection Of Ige And Igg Antibodies To H Lineatum

      For detection of IgE antibodies, an extract of H lineatum first instar larvae (HL1; 104 mg/mL) was bound to paper disks and allowed to react with 0.050 mL of serum.
      • Yunginger JW
      • Adolphsoll CR
      Standardization of allergens.
      After washing, IgE antibodies were detected with radiolabeled anti-IgE. To measure IgG antibodies, HL1 bound to microtiter plates was reacted with diluted serum.
      • Mathews HM
      • Walls KW
      • Huong AY
      Microvolume, kinetic-de pendent enzyme-linked immunosorbent assay for amoeba antibodies.
      Bound IgG antibody was detected by the enzyme-linked immunosorbent assay (ELISA).
      • Prutte JH
      • Barrett CC
      • Fisher WF
      Kinetic development of scrum antibody to puri fied Hypoderma lineatum proteins in vaccinated and nonvaccinated cattle.
      The elevated levels of IgE and IgG antibodies for HL1 antigens on February 22 (about 2 months after worm emergence) and in June 1996 are shown in Table 1. Among the IgG subclasses, antibodies of the IgG4 subclass dominated but decreased between February and June.
      Table 1IgE and IgG Antibodies to Extract of Hypoderma lineatum First Instar Larvae
      IgE Response
      To verify specificity, the patient's serum was added to mixtures of solid-phase and various volumes of fluid-phase extract of H lineatum first instar larvae (HL1); bound IgE was detected with radiolabeted anti-IgE. An extract of natural rubber latex, an unrelated antigen, was used as a fluid-phase negative control for the inhibition experiments. Fluid-phase HLI extract inhibited the binding of IgE with the solid-phase HLI; in contrast, natural rubber latex extract did not.
      Test serumRadioactive counts bound
      Results are means of duplicates.
      % Total counts added (% negative control)
      Control
      The control serum was from a man with no history of atopy, no exposure to H lineatum, and low total IgE antibody.
      48311.65(100)
      Patient (2/22/96)
      About 2 months after emergence of the worm.
      36,97212.62(765)
      Patient (6/11/96)37,36712.75 (773)
      IgG Response
      IsotypePatient Subclass (2/22/96)
      Results presented as kinetic enzyme-linked immunosorbent assay slope + SD (duplicate or triplicate determinations).
      Patient (6/11/96)
      Human control serum from Sigma Chemical Co, St Louis, Mo (No. H1388), clotted male whole blood, nonreactive for human immunodeficiency and hepatitis B and C viruses.
      Negative control
      Human control serum from Sigma Chemical Co, St Louis, Mo (No. H1388), clotted male whole blood, nonreactive for human immunodeficiency and hepatitis B and C viruses.
      IgG177±5119±51.73±0.32
      γ10.40±0.130.23±0.21−0.23±0.55
      γ21.60±0.280.77±0.340.52±0.55
      γ30.10±0.130.15±0.000.3310.33
      γ455.3±5.521.3±0.90.05±0.09
      * To verify specificity, the patient's serum was added to mixtures of solid-phase and various volumes of fluid-phase extract of H lineatum first instar larvae (HL1); bound IgE was detected with radiolabeted anti-IgE. An extract of natural rubber latex, an unrelated antigen, was used as a fluid-phase negative control for the inhibition experiments. Fluid-phase HLI extract inhibited the binding of IgE with the solid-phase HLI; in contrast, natural rubber latex extract did not.
      Results are means of duplicates.
      The control serum was from a man with no history of atopy, no exposure to H lineatum, and low total IgE antibody.
      § About 2 months after emergence of the worm.
      Results presented as kinetic enzyme-linked immunosorbent assay slope + SD (duplicate or triplicate determinations).
      Human control serum from Sigma Chemical Co, St Louis, Mo (No. H1388), clotted male whole blood, nonreactive for human immunodeficiency and hepatitis B and C viruses.

      Western Blot Analyses For H Lineatum Antigens

      Electrophoresis with use of 12% polyacrylamide gels with sodium dodecyl sulfate separated 8 to10 protein bands in HL1 (Figure 3, A). After being blotted onto nitrocellulose, the proteins were reacted with the patient's serum and developed with either radiolabeled anti-IgE or staphylococcal protein A.
      • Harlow E
      • Lane D
      These immunoblots revealed IgE and IgG antibodies for various HL1 proteins (Figure 3, B and C), indicating a heterogeneous antibody response.
      Figure thumbnail gr3
      Figure 3Sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blot analyses of extract of Hypoderma lineatum first instar larvae (HL1) and patient's serum. A, The 12% polyacrylamide gel shows marker proteins in the left and right lanes with molecular mass listed in kd; 50 μg of HL1 was applied to the gel, and the gel was stained with Coomassie blue. B, After Western blotting and exposure to the patient's serum, the membrane was developed with radiolabeled anti-IgE; exposure time was 5 hours. C, After Western blotting and exposure to the patient's serum, the membrane was developed with radiolabeled staphylococcal protein A. The immunoblot was exposed for 45 minutes. In blots made with serum from a normal nonexposed individual, only faint staining of 3 bands appeared after 16 hours (results not shown).

      Discussion

      H lineatum, the common cattle grub or warble botfly, and Hypoderma bovis, the northern cattle grub, are obligate insect parasites of cattle. Losses from these parasites are estimated at $66 million per year, primarily as a result of damaged hides.
      • Drummond RO
      Economic aspects of ectoparasites of cattle in North America.
      In January or February, depending on the latitude, the adult H lineatum female fly, the only species native to Texas, attaches eggs at the base of host hairs with a specialized ovipositor.
      • Cogley TP
      • Anderson JR
      • Weintraub J
      Ultrastructure and function of the attachment organ of warble fly eggs (Diptera: Oestridac: Hypodermatinae).
      Eggs hatch in approximately 3 to 7 days.
      • Pruett JH
      • Kunz SE
      Thermal requirements for Hypoderma lineatum (Diptera: Ocstridae) egg development.
      In February through April, the newly hatched first instar larvae penetrate the skin via the hair follicles and migrate during April through June to connective tissue sites around the diaphragm and esophagus. The larva resides there approximately 4 months, then (in September or October) migrates to the subcutaneous tissues of the back. During October through December, each larva digests a breathing hole and resides in a furuncle (warble) for about 2 months, where it molts twice. The larva exits the host, pupates in loose soil, and develops to the adult fly stage.
      • Scholl PJ
      Biology and control of cattle grubs.
      I Remarkably, in our patient, the larval survival time was consistent with the cow host, even though the human is an aberrant host.
      Although patients with myiasis due to H lineatum or H bovis have been described previously,
      • Uttamchandani RB
      • Trigo LM
      • Poppiti Jr, RJ
      • Rozen S
      • Ratzan KR
      Eosinophilic pleural effusion in cutaneous myiasis.
      • Scott HG
      Human myiasis in North America (1952-1962 inclusive).
      • Navajas A
      • Cardinal J
      • Piñan MA
      • Ortiz A
      • Astigarraga I
      • Fdcz-Tcijeiro A
      Hypereosinophilia due to myiasis.
      • Hampel H
      • Putz A
      • Müller N
      Major depression following myiasis with hypereosinophilic syndrome.
      the incidence of this disease is difficult to assess because most cases are probably never reported.
      • Scott HG
      Human myiasis in North America (1952-1962 inclusive).
      Several cases of myiasis have been documented among farmworkers in France.
      • Doby JM
      • Quilici M
      • Mary C
      • Deunff J
      Comparative value of immu-noclectrophoresis and ELISA in the serological diagnosis of human hypodermyiasis [in French].
      Immunoelectrophoresis and ELISA can serologically diagnose human hypodermiasis
      • Boulard C
      • Petithory J
      Serological diagnosis of human hypo-dermosis: a preliminary report.
      • Doby JM
      • Quilici M
      • Mary C
      • Deunff J
      Comparative value of immu-noeleclrophoresis and ELISA in the serological diagnosis of human hypodermyiasis [in French].
      ; sera from patients with other parasitosis showed no response to H lineatum antigens.
      • Boulard C
      • Petithory J
      Serological diagnosis of human hypo-dermosis: a preliminary report.
      These tests use soluble proteolytic enzymes extracted from the first instar larva as antigens.
      • Boulard C
      Anatomie et histologie du tube digestif de la larvae d'Hypoderma bovis (Diptere Oestriforme).
      The larval collagenase molecule contains the most commonly shared epitopes between the soluble antigens of H lineatum tum and H bovis.
      • Pruett JH
      • Scholl PJ
      • Tcmeyer KB
      Shared epilopes between the soluble protcins of Hypoderma lineatum and Hypoderma bovis first instars.
      The H lineatum collagenase (hypodermin C) has been thoroughly studied.
      • I^croisey A
      • Boulard C
      • Keil B
      Chemical and enzymatic characterization of the collagenase from the insect Hypoderma lineatum.
      An ELISA diagnostic test that uses antibodies specific for hypodermin C should be diagnostic for human hypodermiasis caused by either species.
      Our patient's immune response included leukocytosis, eosinophilia, elevated total IgE level, degranulation of tissue eosinophils, and increased IgE and IgG antibodies specific for the HL1 antigens. Of note, his IgG titer decreased between February and June 1996; an increasing titer should indicate ongoing infection. Interestingly, the IgG response was mainly IgG4, the predominant blocking antibody in chronic helminth infections.
      • Hussain R
      • Poindexter RW
      • Ottesen EA
      Control of allergic reactivity in human filariasis: predominant localization of blocking antibody to the IgG4 subclass.
      Prolonged antigenic stimulation, eg, allergy immunotherapy and allergic bronchopulmonary aspergillosis, is probably important in stimulating IgG4 production.
      • Nakagawa T
      • Kozeki H
      • Katagiri J
      • et al.
      Changes of house dust mite-specific IgE, lgG and IgG subclass antibodies during immu-notherapy in patients with perennial rhinitis.
      • Tomee JF
      • Dubois AE
      • Koeter GH
      • Beaumont F
      • van der Werf TS
      • Kauffman HF
      Specific IgG4 responses during chronic and transient antigen exposure in aspergillosis.
      Several features of our patient's illness suggested the idiopathic hypereosinophilic syndrome. This syndrome covers a heterogeneous patient group, with an idiopathic (no apparent causes such as parasitic infections or allergic diseases), sustained (>6 months) elevated eosinophil count (>1.5 × 109/L) and signs and symptoms of organ involvement.
      • Weiler PF
      • Bubley GJ
      The idiopathic hypereosinophilic syndrome.
      Indeed, the diagnosis in our patient was the hypereosinophilic syndrome, and glucocorticoid therapy was initiated. This syndrome has been diagnosed previously in patients with H lineatumr
      • Uttamchandani RB
      • Trigo LM
      • Poppiti Jr, RJ
      • Rozen S
      • Ratzan KR
      Eosinophilic pleural effusion in cutaneous myiasis.
      • Hampel H
      • Putz A
      • Müller N
      Major depression following myiasis with hypereosinophilic syndrome.
      and H bovis infections.
      • Navajas A
      • Cardinal J
      • Piñan MA
      • Ortiz A
      • Astigarraga I
      • Fdcz-Tcijeiro A
      Hypereosinophilia due to myiasis.
      One patient
      • Uttamchandani RB
      • Trigo LM
      • Poppiti Jr, RJ
      • Rozen S
      • Ratzan KR
      Eosinophilic pleural effusion in cutaneous myiasis.
      had a pleural effusion and substantial thickening of subcutaneous tissue and musculature of the lower abdominal wall; the biopsy specimen had granulomatous inflammation and changes consistent with eosinophilic panniculitis. In our patient, evaluation of the skin, subcutaneous tissue, and muscle biopsy specimens suggested eosinophilic fasciitis. Immunofluorescence staining for MBP was strongly positive in the specimens from the deep dermis, subcutaneous tissue, fascia, and muscle of the patient's upper back area. Major basic protein from eosinophil granules is toxic in vitro for helminths.
      • Popken-Harris P
      • Thomas L
      • Oxvig C
      • et al.
      Biochemical properties, activities, and presence in biologic fluids of eosinophil granule major basic protein.
      Our patient had bilateral pleural effusions, an occasional finding in the hypereosinophilic syndrome. Furthermore, CT showed moderate pericardial effusion; echocardiography confirmed this effusion. While uncommon, a pericardial effusion has been reported previously in 1 patient with the hypereosinophilic syndrome.
      • Takamizawa M
      • Iwata T
      • Watanabe K
      • et al.
      Elevated production of interleukin-4 and interleukin-5 by T cells in a child with idiopathic hypereosinophilic syndrome.
      Of interest, Panciera et al
      • Panciera RJ
      • Ewing SA
      • Johnson EM
      • Johnson BJ
      • Whitenack DH
      Eosinophilic mediastinitis, myositis, pleuritis, and pneumonia of cattle associated with migration of first-inslar larvae of Hypoderma lineatum.
      described eosinophilic mediastinitis, myositis, pleuritis, and pneumonia in cattle infected with H lineatum. Notable similarities in symptoms and chronology exist between the illness in cattle and in our patient's illness.
      Cattle grubs have been controlled chemically since the 1950s by treating cattle with organophosphorus insecticides and recently with ivermectin.
      • Scholl PJ
      Biology and control of cattle grubs.
      Cattle grubs are susceptible to ivermectin; 100% cattle grub control can occur with doses between 0.2 and 200 μg/kg.
      • Drummond RO
      Control of larvae of the common cattle grub (Diptcra: Oesiridae) with animal systemic insecticides.
      In West Africa, ivermectin has been used in humans to control Onchocerca volvulus, a filarial parasite causing blindness and chronic dermatitis.
      • Aziz MA
      • Diallo S
      • Diop IM
      • Lariviere M
      • Porta M
      Efficacy and tolerance of ivermectin in human onchocerciasis.
      • Greene BM
      Modern medicine versus an ancient scourge: progress toward control of onchocerciasis.
      Ivermectin at a dose of 200 ug/kg has been effective in human myiasis.
      • Hampel H
      • Putz A
      • Müller N
      Major depression following myiasis with hypereosinophilic syndrome.
      • Jelinek T
      • Nolhdurfl HD
      • Rieder N
      • Löscher T
      Cutaneous myiasis: review of 13 cases in travelers reluming from tropical countries.
      In humans, localized larvae can be removed either by gentle pressure around the warble or surgically. Occlusive dressings over the punctum of the swelling may induce the larvae to emerge. Secondary bacterial infection should be treated with debridement or drainage and appropriate antibiotics.
      • Uttamchandani RB
      • Trigo LM
      • Poppiti Jr, RJ
      • Rozen S
      • Ratzan KR
      Eosinophilic pleural effusion in cutaneous myiasis.
      In summary, physicians should suspect H lineatum in patients who live in an area near cattle and who develop eosinophilia in association with myalgias, migratory swellings, pleuritis, pericarditis, and furunculosis. The diagnosis can be confirmed by IgE and IgG responses to H lineatum antigens. Treatment with ivermectin at a dose of 200 ug/kg is beneficial.
      • Hampel H
      • Putz A
      • Müller N
      Major depression following myiasis with hypereosinophilic syndrome.
      • Jelinek T
      • Nolhdurfl HD
      • Rieder N
      • Löscher T
      Cutaneous myiasis: review of 13 cases in travelers reluming from tropical countries.

      Acknowledgments

      We thank Richard T. Jones for performing the IgE antibody immunoassays and immunoblotting experiments, Gail M. Kephart for immunofluorescent staining of the biopsy tissues, Brenda Burkett for valuable assistance in performing the kinetic ELISA, Linda H. Arneson for secretarial assistance, and Cheryl R. Adolphson for editorial assistance.

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