Case 1: Drug-induced eosinophilic pneumonia
Jennifer Gauntt, MD, ACP Resident/Fellow Member
A 17-year-old male presented with shortness of breath, nonproductive cough, pleuritic chest pain and fatigue, all of three days' duration. His medical history was otherwise significant for two prior episodes of pneumonia requiring hospitalization, seasonal allergies on occasional antihistamines, and acne vulgaris. Upon initial presentation, his oxygen saturation was 92% on room air, and results of chest radiography were consistent with multilobar pneumonia. The patient was admitted to the hospital and improved after completing a five-day course of levofloxacin. He was discharged on his home medication of minocycline, which he had been taking for acne vulgaris.
The patient's symptoms recurred 24 hours after discharge, and he presented to the Emergency Department two days later with worsening cough and dyspnea. On physical exam, he was ill-appearing, febrile, tachycardic and tachypneic, with oxygen saturation of 95% on room air. The pulmonary examination was significant for decreased aeration and bibasilar crackles. The remainder of the physical examination was unremarkable.
Laboratory testing demonstrated an elevated white blood cell count of 17,500 µ/L with 22% eosinophils. Comprehensive metabolic panel, urinalysis, hemoglobin, hematocrit and platelet count were normal. Chest radiography showed interval improvement compared to his previous X-ray a week prior. Computed tomography (CT) scan of the chest demonstrated bilateral ground-glass and consolidative opacities, predominantly in the periphery. Serum IgE level was greater than two standard deviations above the mean. Bronchoalveolar lavage (BAL) demonstrated 91% eosinophils, confirming an eosinophilic pneumonia.
The diagnosis in this case is minocycline-induced eosinophilic pneumonia. The differential diagnosis of pulmonary eosinophilia includes Churg-Strauss syndrome, parasitic infection, allergic bronchopulmonary aspergillosis and drug-induced eosinophilic pneumonia. First described in 1979, minocycline-induced eosinophilic pneumonia is rare, with only approximately 50 cases reported worldwide. Most case reports are from Japan, where minocycline is a more commonly used antibiotic. Minocycline-induced eosinophilic pneumonia is usually characterized by systemic symptoms (including dry cough, fever, pleuritic chest pain and fatigue), peripheral eosinophilia and pulmonary infiltrates within days to weeks of beginning minocycline.
The pathophysiology of the disorder is unknown. On presentation, the condition is often confused with infectious pneumonia, leading to treatment with antibiotics, as in this case. Upon further evaluation, patients with minocycline-induced eosinophilic pneumonia demonstrate leukocytosis with peripheral eosinophilia, elevated serum IgE level, bilateral pulmonary infiltrates on chest X-ray, ground-glass opacities on chest CT, and pulmonary eosinophilia on BAL.
Generally the only treatment necessary for this disorder is discontinuation of minocycline therapy. Rarely, prednisone is required if severe hypoxia or respiratory failure results. While there is no specific diagnostic test for minocycline-induced eosinophilic pneumonia, some cases have been reported in which patients were “rechallenged” with minocycline (inadvertently or intentionally) after initial improvement. Recurrence of their symptoms after “rechallenge” was considered diagnostic of minocycline-induced eosinophilic pneumonia. After re-evaluation of this patient's history, it became clear that he initially improved not because of antibiotics but because he did not receive minocycline while hospitalized. The patient inadvertently “rechallenged” himself at home after resuming minocycline therapy and only subsequently improved after the minocycline was withdrawn permanently.
Dr. Gauntt is the med-peds co-chief resident for 2013-2014 at Christiana Care Health System in Newark, Del.
- Minocycline is an important, albeit rare, cause of eosinophilic pneumonia and mimics an infectious pneumonia.
- Recognition of minocycline as an inciting agent is critical to avoid exposing a patient to unnecessary treatment with antibiotics; withdrawal of the medication is usually the only treatment required.
Case 2: Squamous-cell carcinoma of the gallbladder
Ezeocke Chukuwuemeka, MD, and Grace Salame, MD
A 54-year-old diabetic woman presented to the ED with hyperosmolar, hyperglycemic nonketotic syndrome. On physical examination, the patient was found to have hepatomegaly with a palpable liver edge 5 cm below the costal margin along with right upper quadrant tenderness. The patient reported no gastrointestinal symptoms on review of systems. A right upper quadrant ultrasound, followed by a triphasic CT of the liver, showed a heterogeneous liver lesion surrounding the gallbladder and a mass arising from the fundus of the gallbladder. Subsequent positron emission tomography (PET) scan showed evidence of increased fluorodeoxyglucose uptake in a multi-lobulated hepatic mass and in the gallbladder.
The patient's hospital course was significant for persistent leukocytosis and intermittent fevers. A CT-guided biopsy of her liver revealed a perforated gallbladder, with a filling defect noted on subsequent hepatobiliary iminodiacetic acid (HIDA) scan. A cholecystostomy tube was inserted, and IV antibiotics were initiated. A core biopsy of the liver was negative for carcinoma and showed neutrophilic infiltrates, sinusoidal dilatation and fibrosis. Given the high index of suspicion for malignancy, the patient underwent a second CT-guided core biopsy of her liver, which yielded similar results.
This patient ultimately was demonstrated to have squamous-cell carcinoma of the gallbladder. A third biopsy via fine needle aspirate revealed the malignancy; immunohistochemical stains revealed positivity for CK 56 and p63, which favor the diagnosis of squamous-cell carcinoma, a hypothesis confirmed by the presence of keratinization on microscopy. A limited review of the literature on squamous-cell carcinoma reveals only a 0.5% to 3% preponderance of this malignancy within gallbladder cancers. The spectrum of gallbladder malignancies includes adenocarcinoma or adenosquamous or squamous histology, as in our patient. There are interesting geographic differences in the prevalence of gallbladder cancer, with highest rates noted in Central and South America, Japan, and certain regions of Europe and India. Treatment of squamous-cell carcinoma of the gallbladder involves surgical resection; however, the disease is usually diagnosed at an advanced stage when surgical intervention is no longer indicated, as was the case in our patient.
Drs. Chukuwuemeka and Salame are second-year residents at St. Louis University Hospital in Missouri.
- Gallbladder cancer is rare in the United States, and squamous-cell histology is even less common.
- The diagnosis in this case was made due to a high index of suspicion for malignancy, resulting in repeated and ultimately conclusive biopsy.
Case 3: Vancomycin-induced thrombocytopenia
Saurabh Sharma, MD, ACP Resident/Fellow Member
A 73-year-old woman with a history of hypertension presented with shortness of breath and fever of three days' duration. Physical examination revealed hypotension, tachycardia and crepitations in the left lower chest. Laboratory testing showed leukocytosis with normal platelet count and elevated creatinine of 3.5 mg/dL. She developed septic shock and eventually required mechanical ventilation in the ICU.
The patient was given IV ceftriaxone, azithromycin and vancomycin. She was also given prophylactic-dose subcutaneous heparin for prevention of deep venous thrombosis. On hospital day 9, the platelet count dropped to 53 × 103/mm3, progressively decreasing to 3 ×103/mm3 on day 11 (see Table). Heparin and all antibiotics, including vancomycin, were stopped. Further investigations showed a normal peripheral blood smear, hepatitis profile, thyroid profile, prothrombin time and partial thromboplastin time. Heparin-induced platelet antibody testing was negative. Serum lactate dehydrogenase, haptoglobin, fibrinogen and D-dimer were also within normal limits. Disseminated intravascular coagulation and heparin-induced thrombocytopenia were therefore ruled out.
Multiple platelet transfusions and IV immunoglobulins were subsequently administered (see Table). Because drug-induced thrombocytopenia was suspected, blood samples were sent to detect antibodies to vancomycin, ceftriaxone and azithromycin by flow cytometry. The patient tested positive for IgG-class vancomycin-dependent platelet-reactive antibodies. IgM antibodies were negative. There were no antibodies found against ceftriaxone or azithromycin. By hospital day 25, the platelet count increased to 87 × 103/mm3 and subsequently normalized.
The patient's diagnosis is vancomycin-induced thrombocytopenia (VIT). Vancomycin is an increasingly recognized cause of drug-induced thrombocytopenia. VIT is caused by drug-dependent, platelet-reactive antibodies of IgG class, IgM class or both. It can easily be overlooked, especially in patients with sepsis and life-threatening infections. Platelet counts can drop as soon as one hour to a few days after exposure to vancomycin; this effect can be reversed completely after withdrawal of the antibiotic. Because vancomycin is renally cleared, the time required for platelets to return to normal may be longer in patients with renal insufficiency. A repeat challenge with vancomycin to confirm the diagnosis of VIT is not recommended, as the repeat episode of thrombocytopenia may lead to severe or even fatal bleeding. Testing for vancomycin-induced antibodies can be helpful in suspected cases of VIT.
Corticosteroids have no proven value in the treatment of VIT. Intravenous immunoglobulin, plasmapheresis and platelet transfusion may help stabilize life-threatening bleeding. Once a drug-induced cause of thrombocytopenia has been detected, patients should be advised to avoid the offending agent because a second exposure can lead to life-threatening bleeding complications. Patient education is very important, and the importance of avoiding repeat exposure should also be documented in the patient's health record to make other practitioners aware of the condition.
Dr. Sharma is a fellow in geriatric medicine at the Mayo Clinic in Rochester, Minn.
- Vancomycin-induced thrombocytopenia (VIT) should be considered in patients with refractory thrombocytopenia during vancomycin treatment.
- Drug-dependent, platelet-reactive antibodies of IgG class, IgM class or both can be detected to diagnose VIT.
Case 4: Vibrio vulnificus septicemia after eating raw oysters
Nynke C. den Hollander, MD, ACP Member, and Juan C. Sarria, MD
A 59-year-old woman with a history of alcoholic cirrhosis of the liver presented to the ED with severe back pain that had started the previous evening. The patient also reported chills, nausea, vomiting and mild right lower quadrant abdominal pain. The patient had cataract surgery performed the day before her presentation. Physical examination was remarkable for a temperature of 101.4°F, and palpation of the spine and paraspinal musculature yielded severe tenderness. There was minimal tenderness on palpation of the right lower abdomen. Laboratory studies showed a white blood cell count of 17,500 cells/µL (reference range, 4,500 to 10,000 cells/µL). CT of the abdomen and pelvis demonstrated findings consistent with her known diagnosis of cirrhosis but was otherwise unremarkable. Ophthalmologic examination reported no abnormal ocular findings related to the recent surgery. The patient was empirically started on metronidazole, cefotaxime and vancomycin. Magnetic resonance imaging (MRI) of the cervical, thoracic and lumbar spine was normal.
Sixteen hours after presentation, blood cultures drawn on admission grew gram-negative bacilli, subsequently identified as Vibrio vulnificus. Upon further questioning, the patient reported that she ate raw oysters on her way home from her cataract surgery. Antibiotics were changed to oral doxycycline and intravenous ceftazidime. On the fifth day of hospitalization, she was discharged in good condition with a 14-day course of oral doxycycline. The patient's back pain resolved completely.
Vibrio vulnificus septicemia is the most common cause of fatalities related to seafood consumption in the United States. Early recognition is vital to decrease mortality, but even with appropriate treatment, mortality rates are as high as 50%. Vibrio vulnificus is a gram-negative rod found in salt water throughout the world, with peak concentrations from March to November due to higher water temperatures. Filter-feeders (including common bivalves such as clams, oysters, scallops and mussels) become contaminated with the bacteria, which are transferred to humans upon ingestion. Symptoms occur within hours after eating raw seafood. Classically, primary Vibrio vulnificus septicemia presents with fever, nausea and vomiting after seafood consumption, but patients can also present with severe musculoskeletal pain, thrombocytopenia, and headache or mental status changes. Patients with cirrhosis are up to 80 times more likely to be infected because alterations in their iron metabolism and portal hypertension result in bacterial translocation. Current guidelines recommend treatment with doxycycline and a third-generation cephalosporin.
Dr. den Hollander is an internist in Galveston, Texas, and Dr. Sarria is an associate professor of infectious diseases at the University of Texas Medical Branch in Galveston.
- Vibrio vulnificus infection can present as primary septicemia after ingestion of raw or undercooked seafood. Without early recognition and treatment, mortality rates are high.
- Patients with cirrhosis are at higher risk and need to be warned about the dangers of raw seafood consumption.
Case 5: Clinically isolated syndrome versus multiple sclerosis
Herbert Ip, MD, ACP Resident/Fellow Member
A 30-year-old man with a history of hypertension presented with progressive double vision that had lasted six days. He initially described this change in vision as occurring only late at night. He reported seeing two images on the television screen, which resolved after blinking his eyes. The patient thought his eyes were “just tired” after working in front of a computer all day. However, after three days he noticed the double vision during daytime hours as well. His wife noticed that his right eye had begun to laterally deviate. He had no associated loss of vision, confirmed by his optometrist. For the three days prior to presentation, he wore an eye patch over his right eye to mitigate his diplopia.
Upon presentation, review of systems was negative for any additional neurological symptoms. Physical examination showed that his right eye deviated from midline superiorly and laterally. A right internuclear ophthalmoplegia was noted with loss of adduction and downward gaze of the right eye. Visual acuity in both eyes was normal, there was no rapid afferent papillary defect, and the pupils were equal to light and accommodation. The remainder of the neurologic examination was completely normal. MRI of the brain revealed several foci of T2 hyperintensity in the right periventricular region, while cervical, thoracic and lumbar spinal images were all normal. Lumbar puncture was negative for infectious processes but demonstrated oligoclonal bands. Intravenous methylprednisolone was administered for three days with complete resolution of his diplopia, and he was subsequently started on glatiramer for disease-modifying therapy.
This patient's MRI and lumbar puncture findings are suggestive of multiple sclerosis (MS). However, because this is his first clinical episode, his initial diagnosis is technically termed “clinically isolated syndrome” (CIS). CIS is defined as the first clinical neurological event lasting more than 24 hours with symptoms and signs suggestive of an inflammatory demyelinating process in the central nervous system. This is considered its own clinical entity, as not all patients with CIS progress to MS. The risk of progression varies depending on the location of associated lesions and can be as high as 85% in patients with optic neuritis or up to 60% in patients with brainstem syndromes.
CIS is commonly seen in adults between the ages of 20 and 40 years, more often women, and with lesions involving the optic nerve, spinal cord, brainstem or cerebellum. The differential diagnosis, in addition to MS, includes acute disseminated encephalomyelitis, neuromyelitis optica, vasculitis, ischemia and compression from tumor. Treatment options for CIS are variable, as many CIS events resolve on their own. Factors that favor treatment include associated visual loss, optic neuritis, significant motor dysfunction or ataxia and brainstem lesions. If acute treatment is indicated, high-dose IV steroids are the standard of care. Both beta-interferon and glatiramer acetate have demonstrated benefits in delaying days to conversion to clinical MS, but data on long-term benefit (over 5 years) are lacking. It is hoped that additional research will elucidate predictive factors that favor CIS conversion to MS and demonstrate the safe use of long-term immunomodulation therapies for prevention.
Dr. Ip is a chief resident of general internal medicine at Lahey Hospital and Medical Center in Burlington, Mass.
- CIS is a clinical syndrome distinct from MS. Early identification and consideration of diagnostic alternatives are important.
- Use of long-term immunomodulatory therapeutics is still being evaluated in CIS, with the goal of mitigating the progression to MS.
Case 6: Quinidine-induced thrombocytopenia purpura
Josh Grossman, MD, FACP
A 33-year-old woman who was 7 months pregnant and had no significant medical history presented with a new rash and blood in her urine. She was taking prenatal vitamins and had also recently and before onset of her new symptoms, begun taking quinidine. She noted taking “a few” tablets per day for what she described as “heart flip-flops.” The quinidine had been prescribed for her deceased mother. There was no family history of coagulopathy. Physical examination on presentation revealed normal vital signs and dry petechiae with purpura on the face and chest. Laboratory testing confirmed suspected thrombocytopenia, with a platelet count of 3,000/µL; white and red blood cell counts, prothrombin time (PT), partial thromboplastin time (PTT) and fibrinogen levels were all within normal limits. The patient was admitted to the hospital and placed on bedrest precautions. Off quinidine and without platelet transfusion, no bleeding events occurred and her platelet count increased to a level of 90,000/µL by the sixth hospital day. Laboratory clot-retraction inhibition testing confirmed the presence of quinidine-induced thrombocytopenia purpura. No insight into the palpitations for which the patient took quinidine was achieved, as this was not a symptom that persisted during her hospitalization. The patient subsequently delivered a full-term healthy baby girl. Testing of cord blood suggested that the quinidine-platelet antibody complex did not cross the placental barrier. The patient was educated about refraining from taking further doses of quinidine and subsequently maintained a normal platelet count.
Quinidine-induced thrombocytopenia purpura has been well described in the medical literature, although most studies are from the 1950s and 1960s. The drug induces a quinidine-platelet antibody complex that binds platelets most commonly at the membrane glycoprotein (GP) Ib/IX complex and yields platelet destruction. Patients have died of this toxicity. Quinidine is an antiarrhythmic medication first used in the 18th century for both atrial and ventricular tachyarrhythmias; it is now used much less commonly due to various toxicities. In addition to the well-described syndrome of cinchonism, there are multiple adverse effects reported on the cardiovascular, neurologic, gastrointestinal and hematologic systems and multiple drug interactions via inhibition of a cytochrome p450 enzyme.
The concern for this patient was clearly heightened by her pregnancy. Quinidine is a category C medication in pregnancy. Although drug-induced thrombocytopenia poses risks to both the mother and fetus, the risk of hemorrhage in pregnant women approximates that of nonpregnant women provided the mother is not severely thrombocytopenic at the time of delivery. Education about complete future avoidance of quinidine is essential, as repeat exposure can result in the return of severe thrombocytopenia in a matter of hours. The phenomenon of patients taking medications not prescribed for them is common, although quinidine is not a typical offender.
“Dr. Josh” is an internist in rural Tennessee and a retired colonel in the U.S. Army Medical Corps.
- Medication-induced thrombocytopenia is common, althovugh quinidine-related thrombocytopenia is not; if undetected, severe thrombocytopenia in pregnancy can pose significant risk of maternal and fetal morbidity and mortality.
- Clinicians must remain vigilant in screening their patients for use of unprescribed medications that might have been prescribed to family members, both living and deceased.
Case 7: Vesicular rash in a patient with myasthenia gravis
David Hirota, MD, FACP, and Stephen Marer, MD
A 69-year-old man with ocular myasthenia gravis, prior alcoholism and recent history of perforated diverticulitis requiring surgical intervention (performed two months prior to this admission) presented with symptoms of altered mental status, low-grade fevers, and a diffuse vesicular rash. After developing multiple vesicular skin lesions, the patient presented to an outpatient dermatologist, and a skin biopsy performed at that visit was inconclusive for a specific diagnosis. The patient was taking prednisone (40 mg) and pyridostigmine for his myasthenia gravis. Upon admission, he had a temperature of 100.0°F and his physical examination was notable for confusion, chronically ill appearance and multiple vesicular lesions covering the face, torso and extremities. The patient was started on broad-spectrum antimicrobials (including IV acyclovir) until a repeat skin-punch biopsy returned positive for Nocardia braziliensis. Multiple blood cultures subsequently returned positive for Nocardia, and CT of the chest revealed multiple cavitary nodules. Brain MRI was negative for any evidence of intracranial abscesses, although the patient was later found on ophthalmologic evaluation to also have retinal involvement. The patient was diagnosed with disseminated nocardiosis and treated with IV and oral trimethoprim/ sulfamethoxazole. The patient also received intraocular antimicrobial injections for his retinal disease. He ultimately improved with prolonged antimicrobial treatment and was later converted to an oral suppressive regimen. The patient also recovered vision in his affected eye.
This patient had disseminated nocardiosis due to steroid-related immunosuppression. Nocardia organisms are ubiquitous in the environment and can be found in both soil and water. Of note, our patient pursued gardening as a primary pastime. The reported incidence of disseminated Nocardia cases is reportedly increasing and chronic immunosuppression (including almost any condition requiring long-term corticosteroid use) is a well-established risk factor for nocardiosis. Disseminated infection is often characterized by widespread abscess formation. The most commonly reported sites of involvement include the central nervous system and eyes, skin and soft tissues, kidneys, bone/joints and heart. Of note, Nocardia organisms grow more slowly than common bacteria, and therefore it may take longer to establish a definitive diagnosis.
Dr. Hirota is a hospitalist with Memorial HealthCare System in Long Beach, Calif. Dr. Marer is a hospitalist at Torrance Memorial Medical Center in Torrance, Calif.
- Consider nocardiosis as a part of the differential diagnosis in an immunocompromised patient presenting with systemic and dermatologic symptoms; sulfonamides remain the mainstay of therapy.
- Contact your microbiology lab in advance if you believe your patient might have nocardiosis, and be aware that the time necessary to grow the organism in culture will be longer than that for common bacteria.