Reader response to "A YOUNG WOMAN WITH RESPIRATORY FAILURE AFTER A VISIT TO COMPOST STATION"

Dear Dr. Falk,

I read with interest the recent posting referenced above. I worry that the authors may have overlooked several important issues. I don't see their emails and hope you will pass this along to them.

1. It is unclear this patient ever had AEP. Patients with CGD don't get colonization of otherwise normal airways. She likely had early invasion by aspergillus and this was blunted by steroids. The steroids did not make her susceptible to aspergillus invasion, rather they blunted her response allowing the delay in critical presentation. In the series reported by Siddiqui (below) patients had similar presentations without antecedent steroids. In fact, even in the setting of killed hyphae CGD physiology leads to severe reactions (Absence of respiratory burst in X-linked chronic granulomatous disease mice leads to abnormalities in both host defense and inflammatory response to Aspergillus fumigatus. Morgenstern DE, Gifford MA, Li LL, Doerschuk CM, Dinauer MC. J Exp Med. 1997 Jan 20;185(2):207-18).
2. The authors suggest that the treatment that got her off the ventilator was the the addition of IFNg to the voriconazole and micafungin. They might review the record to date the improvement in her ventilatory parameters and whether the initiation of steroids were associated with it.
3. This syndrome has been well documented (Fulminant mulch pneumonitis: an emergency presentation of chronic granulomatous disease. Siddiqui S, Anderson VL, Hilligoss DM, Abinun M, Kuijpers TW, Masur H, Witebsky FG, Shea YR, Gallin JI, Malech HL, Holland SM. Clin Infect Dis. 2007 Sep 15;45(6):673-81).

Steve Holland

Chief, Laboratory of Clinical Infectious Diseases CRC B3-4141 MSC 1684 Bethesda, MD 20892-1684
301-402-7684 (v)
301-480-4508 (fax)
smh@nih.gov
Assistant: Adrienne Woodworth
301-451-9019 (v)
301-480-4506 (fax)
awoodworth@niaid.nih.gov

Dear Dr. Falk

I am grateful for Dr. Holland’s interest and astute observation with respect to our recent case report entitled "A young woman with respiratory failure after visiting a compost station."  Dr. Holland specifically made three observations.  First, he notes that it's unclear whether the patient ever had acute eosinophilic pneumonia (AEP).  Second, he appropriately points out that fulminant mulch pneumonitis had previously been described (1). Finally, he calls into question whether the addition of IFN-gamma to the voriconazole and microfungin may have assisted in improving the patient's ventilatory parameters.  I have addressed these points below.

The question as to whether the patient ever had AEP is reasonable to raise especially when the case is reviewed in retrospect. However, there are some unique aspects of our case which should be considered before dismissing AEP as a serious diagnostic consideration. 

Acute fulminant fungal pneumonia, particularly invasive aspergillus pneumonia (IPA), is a known potentially fatal infection in patients with chronic granulomatous disease. (1, 2) The patient in our case presented with a febrile illness, dyspnea, hypoxia, and bilateral nodular/ground-glass infiltrates shortly after visiting a compost station.  A clinician evaluating such findings in a patient with known chronic granulomatous disease (CGD) should be concerned about a possible opportunistic infection such as IPA.   Our patient, however, was not known to have CGD at the time of presentation.  Therefore, the working diagnosis of AEP was quite reasonable as the patient met diagnostic criteria of this disorder. (3) 

Our patient presented with acute febrile illness associated with bilateral infiltrates, and elevated peripheral eosinophilia, an elevated eosinophil count on bronchoalveolar lavage, and an elevated peripheral IgE.  No fungal elements were noted on initial bronchoscopy.  While an open lung biopsy was not performed at that time and may have added a diagnostic element, some have argued that in the setting establishing the remaining AEP criteria, a lung biopsy may not be warranted before initiating therapy with steroids. (4)  Further, it is typical for AEP to dramatically improve with steroid treatment such that infiltrates, fever, hypoxia and eosinphilia resolve in a matter of days. (5, 6) Our patient’s initial clinical course was no different. Not only did her fever, hypoxia and serum studies improve but her infiltrates completely resolved in 48 hours.

While the patient’s initial presentation is consistent with AEP, such a diagnosis can retrospectively be called into question once she developed IPA and the diagnosis of CGD was subsequently established. In patients with CGD, exposure to certain pathogens including Aspergillus species can cause a granulomatous reaction is various organs including the lungs and this reaction can be steroid responsive.(7)  In fact, there are several reports of successfully treating CGD patients for refractory infections with the addition of glucocorticoids. (1)  Therefore, Dr. Holland’s observation that it is unclear whether this specific patient ever had AEP is certainly reasonable.  However, there is one essential difference between our patient’s clinical course and other similar presenting patients described in the literature. (1) In Siddiqui’s mulch pneumonitis case series (1),  none of the 9 patients described had a complete clinical and radiographical response to corticosteroids within days of presentation as was seen in our patient. In fact, we are aware of only one other reported case (8) of a patient (with previously undiagnosed CGD) who initially presented with eosinophilic infiltrates essentially fulfilling all of the diagnostic criteria of AEP (3) and who later developed invasive pulmonary aspergilosis.  Like our patient, Trawick et al (8) describes a patient who presented with what appeared to be an acute eosinophilic pneumonia without any evidence of infection (including aspergillus) after working in a yard with compost. The patient’s fever, hypoxia and infiltrates improved within 24 hours of steroid initiation and the patient was discharged. Unfortunately, the patient returned three days later with recurrent symptoms and infiltrates. At that time, cultures grew Aspergillus and septate hyphae where noted on a lung biopsy. The presence of IPA prompted further investigation and the diagnosis of CGD. Another reported case describes a patient who presented with what appeared to be an AEP who subsequently developed IPA despite initial improvement with steroids (9). The patient in the later case, however, was not confirmed to have CGD.

The definitive etiology of AEP is unknown but some have suggested that it is an acute hypersensitivity reaction to an unidentified inhaled antigen (10, 11).  Aspergillus has been shown to cause pulmonary inflammation in both mice (12) and rats (13) and has been implicated as the possible inhaled antigen to cause AEP in a human (14).  While such reports have not necessarily dominated the literature, the implication that aspergillus may be a possible antigen in AEP taken together with our patient’s clinical presentation consistent with AEP after a massive exposure to spores may suggest that CGD patients can present with a hypersensitivity-like-response with eosinophilia before developing IPA. Perhaps if this acute hypersensitivity event is treated early in the course of the illness, patients will demonstrate initial improvement as observed in our case and others (8). As Dr. Holland points out, inflammatory responses develop in mice with CGD in the setting of killed hyphae (15) and such responses may respond to steroids.

In short, we contend that our patient clearly presented with an illness that met the criteria for AEP (3) and that some subtle yet important differences exist between our case and the case series cited by Dr. Holland. (1) 

With respect to Dr. Holland’s point regarding IFN-gamma, I humbly disagree that our manuscript suggested that it was the addition of this agent to voriconozol and micafungin that ultimately assisted in liberating the patient from ventilator support.  While it is true that IFN-gamma was added to the medical regiment at the suggestion of a renowned expert in the field, the manuscript only mentions the additional treatment to describe the patient’s clinical course and does not suggest that it was a major contributing factor in ventilator liberation. In fact, our manuscript highlights the controversy of using IFN-gamma in the acute setting (16) and it discusses the agent’s use in the prophylactic arena for CGD patients. (17, 18)  I suggest that our patient’s slow but steady improvement was the result of many factors including rapidly recognizing that the there was clearly “more than meets the eye” when a seemingly otherwise healthy woman re-presented with what can be considered an opportunistic infection and subsequently diagnosing the CGD coupled the well coordinated critical care team that micromanaged her multi-organ failure to eventual improvement. Coordinating this care with regional and national experts in the field of CGD also played a key role in her recovery.  The antifungal agents, steroids and perhaps the IFN-gamma, were only part of the equation.

We feel our manuscript achieved its specific learning objects as outlined. Perhaps two additional points can be made: 1) aspergillus may be at least one of the unidentified inhaled antigens that can cause AEP and 2) it is imperative to monitor a patient’s course of  therapy when treated with steroids, even if there is initial improvement,  in order to distinguish between patients with  a congenital neutrophil disorder from an uncomplicated case of AEP. (8)

Again, I appreciate the opportunity to respond to the comments of such a renowned investigator and clinician as Dr. Holland.  Please do not hesitate to contact me should you have any further questions.

Thank you,

Timothy N. Liesching, MD

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